Therapeutic uses of selected pyrazolopyrimidine compounds with anti-mer tyrosine kinase activity

ABSTRACT

Pyrazolopyrimidine compounds, methods of use, and processes for making compounds with anti-Mer tyrosine kinase activity comprising Formula I, II, III, IV, or a pharmaceutically acceptable composition, salt, isotopic analog, or prodrug thereof, are provided. The pyrazolopyrimidine compounds described herein have Mer tyrosine kinase (MerTK) inhibitory activity and are useful as anti-infective agents, immunostimulatory and immunomodulatory agents, anti-cancer agents (including against MerTK −/− tumors and ITD and TKD mutant forms of Acute Myeloid Leukemia (AML)), and as adjunctive agents in combination with chemotherapeutic, radiation or other standard of care for neoplasms.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.61/978,268 filed Apr. 11, 2014, U.S. Provisional Application No.61/978,281 filed Apr. 11, 2014, U.S. Provisional Application No.61/978,290 filed Apr. 11, 2014, U.S. Provisional Application No.61/978,321 filed Apr. 11, 2014, U.S. Provisional Application No.61/978,443 filed Apr. 11, 2014, U.S. Provisional Application No.61/978,485 filed Apr. 11, 2014, U.S. Provisional Application No.61/978,513 filed Apr. 11, 2014, U.S. Provisional Application No.61/994,384 filed May 16, 2014, and U.S. Provisional Application No.62/088,159 filed Dec. 5, 2014. The entirety of each of theseapplications is hereby incorporated by reference for all purposes.

GOVERNMENT INTEREST

The U.S. Government has rights in this invention by virtue of supportunder Contract No. HHSN261200800001E awarded by the National Cancerinstitute, National Institute of Health.

FIELD OF THE INVENTION

The present invention is directed to the use of selectedpyrazolopyrimidine compounds having Mer tyrosine kinase (MerTK)inhibitory activity as anti-infective agents, immunostimulatory andimmunomodulatory agents, anti-cancer agents (including against MerTK −/−tumors and ITD and TKD mutant forms of Acute Myeloid Leukemia (AML)),and as adjunctive agents in combination with chemotherapeutic, radiationor other standard of care for neoplasms.

BACKGROUND OF THE INVENTION

MerTK is a member of a receptor tyrosine kinase (RTK) family known asTAM, which also includes AXL and TYRO3. Each member of the TAM familycontains an extracellular domain, a transmembrane domain and a conservedintracellular kinase domain. MerTK was first discovered in thelaboratory of H. Shelton Earp at the University of North Carolina in1994 (Graham et al., Cloning and mRNA expression analysis of a novelhuman proto-oncogene, c-mer. Cell Growth Differ 5, 647-657 (1994)). TheTAM family members undergo ligand-induced homodimerization, followed bycatalytic tyrosine kinase activation and intracellular signaling.Cross-phosphorylation has also been demonstrated within this RTK family,suggesting heterodimerization can occur also. These RTKs are widelyexpressed in many epithelial tissues and in cells of the immune,nervous, and reproductive systems. MerTK was given its name by the Earplaboratory because it was found to be expressed in monocytes and intissues of epithelial and reproductive tissue.

As described in more detail below, ligand-bound MerTK can complex withphosphatidyl serine and it binds apoptotic cells which triggersingestion and suppresses inflammatory cytokines. It is aberrantlyexpressed in certain cancers (for example, acute leukemia (ALL and AML)and some solid tumors (for example melanoma, breast cancer, coloncancer, non-small cell lung carcinoma, glioblastoma and others).

The MerTK ligands include growth arrest-specific 6 protein (GAS6; Chen,et al; Oncogene (1997) 14, 2033-2039), protein-S, tubby and tubby-likeprotein-1 (TULP1), and galectin-3. Several of these ligands are presentin serum and expressed locally in a number of tissues. These ligandsbind to the extracellular domain of MerTK, resulting in tyrosine kinaseactivation.

Since the discovery of MerTK in the Earp laboratory in 1994, there hasbeen a growing body of literature and patents that suggest thepossibility of MerTK as a druggable target for a number of indications.

TAM receptor tyrosine kinases have been investigated for theirinvolvement in certain infectious diseases. Shimojima, et al., reportedthe involvement of members of the Tyro3 receptor tyrosine kinase family,Axl, Dkt and MerTK, in the cell entry of filoviruses Ebolavirus andMarburgvirus, and concluded that each Tyro3 family member is likely acell entry factor in the infection (“Tyro3 Family-mediated Cell Entry ofEbola and Marburg Viruses” Journal of Virology, October 2006 p.10109-10116).

U.S. Pat. No. 8,415,361 to Lemke, et al. (claiming priority to a Nov. 9,2007 provisional application), assigned to The Salk Institute forBiological Studies, describes the use of TAM receptor inhibitors asantimicrobials. In particular, the '361 patent reports that inhibitionof the TAM pathway in virally infected macrophages from TAM tripleknock-out mice leads to reduced levels of infection with a variety ofpseudotyped viruses with either filoviral, retroviral or rhabdoviralglycoproteins. Brindley, et al., reported that in a bioinformatics-basedscreen for cellular genes that enhance Zaire ebolavirus (ZEBOV)transduction, AXL mRNA expression strongly correlated with ZEBOVinfection (“Tyrosine kinase receptor Axl enhances entry of Zaireebolavirus without direct interactions with the viral glycoprotein”Virology, 415 (2011) 83-84).

Morizono, et al, published that Gas6 mediates binding of the virus totarget cells by bridging virion envelope phosphatidyl serine to Axl onthe target cells. Replication of vaccinia virus, which was previouslyreported to use apoptotic mimicry to enter cells, is enhanced by Gas6,and Morizono asserts that these results reveal an alternative molecularmechanism of viral entry that can broaden host range and enhanceinfectivity of enveloped viruses (“The Soluble Serum Protein Gas6Bridges Virion Envelope Phosphatidylserine to the TAM Receptor TyrosineKinase Axl to mediate Viral Entry” Cell Host & Microbe 9, 286-298,2011). In 2014, Morizono and Chen reported that virus binding by viralenvelope phosphatidyl serine is a viral entry mechanism generalized to anumber of families of viruses (Morizono and Chen, “Role of PhosphatidylReceptors in Enveloped Virus Infection”, J. Virology Vol 88(8),4275-4290 (Jan. 29, 2014)).

WO2013/124324 filed by Amara et al. (priority date Feb. 21, 2012), andassigned to Institut National De La Sante et De La Recherche Medicale,reports that Dengue virus is mediated by the interaction betweenphosphatidylserine at the surface of the Dengue viral envelope and TAMreceptors present at the surface of the host cell, and that suchinteraction can be blocked, thereby inhibiting entry of Dengue into hostcells. They also report that the interaction between phosphatidyl serineand TAM receptors is used by other flaviviruses such as Yellow Fever,West Nile and perhaps Chikungunya. Amara focuses on antisense, siRNA andantibody approaches.

Similarly, Bhattacharayya et al., reports that several human viruses,for example Ebola, Dengue, and HIV, externalize PtdSer on their capsidduring budding and use phosphatidylserine to bind to and activate TAMRTKs in the presence of TAM ligands, allowing entry of the virus intocells and furthermore, activation of MerTK in macrophages in response toviral particles expressing PtdSer stimulates an anti-inflammatorycytokine profile as if apoptotic material was being ingested, therebyinhibiting the anti-viral immune response. Bhattacharayya et al observethat TAM receptors are engaged by viruses to attenuate type 1 interferonsignaling (“Enveloped viruses disable innate immune responses indendritic cells by direct activation of TAM receptors”, Cell Host &Microbe 14, 136-147 (2013)). See also Meertens, L. et al. The TIM andTAM families of phosphatidylserine receptors mediate dengue virus entry.Cell Host Microbe 12, 544-557, doi:10.1016/j.chom.2012.08.009 (2012).Mercer, J. & Helenius, A. Vaccinia virus uses macropinocytosis andapoptotic mimicry to enter host cells. Science 320, 531-535,doi:10.1126/science.1155164 (2008).

MerTK is ectopically expressed or overexpressed in a number ofhematologic and epithelial malignant cells. Expression of MerTK and GAS6correlates with poor prognosis and/or chemoresistance in these tumortypes. The mechanisms by which increased MerTK signaling in tumor cellscontributes to tumor malignancy, however, remain unclear.

WO2013/052417 titled “Pyrrolopyrimidine Compounds for the Treatment ofCancer” filed by Wang, et al., and assigned to the University of NorthCarolina describe pyrrolopyrimidines with MerTK inhibitory activity forthe treatment of tumors such as myeloid leukemia, lymphoblasticleukemia, melanoma, breast, lung, colon, liver, gastric, kidney,ovarian, uterine and brain cancer, wherein the pyrrolopyrimidines havethe general structures below, with R substituents as defined in thethose applications:

In November 2013, Dr. Stephen Frye presented data showing the inhibitoryeffects of a pyrrolopyrimidine compound (UNC2025) in non-small cell lungcancer cell lines, MerTK-expressing AML cell lines, and MerTK-negativeAML cell lines. In addition, the effect of UNC2025 was analyzed in anALL 697 cell line xenograft model and a FLT3-ITD AML patient xenograftmodel. Frye, S. “Academic Drug Discovery and Chemical Biology”,Presentation at the Northwestern 18th Annual Drug Discovery Symposium.November 2013. The structure of the pyrrolopyrimidine compound UNC2025is:

WO2011/146313 and WO2014/062774, both titled “PyrazolopyrimidineCompounds for the Treatment of Cancer” filed by Wang, et al., andassigned to the University of North Carolina describepyrazolopyrimidines with MerTK inhibitory activity for the treatment oftumors such as myeloid leukemia, lymphoblastic leukemia, melanoma,breast, lung, colon, liver, gastric, kidney, ovarian, uterine and braincancer, wherein the pyrazolopyrimidines have the general structuresbelow, with R substituents as defined in the applications:

WO2014/062774 further discloses pyrazolopyrimidine compounds for use ina method of treating or inhibiting blood clot formation.

In January 2012, Liu, J, et al., published a comparison of the activityof forty four pyrazolopyrimidine compounds against MerTK, Axl and Tyro3kinases. One of these compounds (UNC569) was tested for inhibition ofMerTK autophosphorylation in human B-ALL cells (“Discovery of NovelSmall Molecule Mer Kinase Inhibitors for the Treatment of PediatricAcute Lymphoblastic Leukemia.” ACS Med Chem Lett. 2012 Feb. 9;3(2):129-134). In May 2013, Schlegel, et al., published results on thepyrazolopyrimidine compound UNC 1062, which reduced activation ofMERTK-mediated downstream signaling, induced apoptosis in culture,reduced colony formation in soft agar, and inhibited invasion ofmelanoma cells (“MER receptor tyrosine kinase is a therapeutic target inmelanoma.” J Clin Invest. 2013 May; 123(5):2257-67).

In December 2013, Zhang, W., et al., also published a comparison of theactivity of forty six 5-arylpyrimidine based compounds for treatment oftumors (“Pseudo-cyclization through intramolecular hydrogen bond enablesdiscovery of pyridine substituted pyrimidines as new Mer kinaseinhibitors.” J. Med. Chem., vol. 56:9683-9692, 2013). These pyrimidinecompounds were identified using a pseudo-ring replacement strategy basedon the previously identified pyrazolopyrimidine MerTK inhibitor, UNC569.

In July 2013, Liu, J, et al. published the first evidence of anti-tumoractivity mediated by a member of this novel class of inhibitors.Specifically, the pyrazolopyrimidine compound UNC1062 inhibited MerTKphosphorylation and colony formation in soft agar (“UNC1062, a new andpotent Mer inhibitor.” Eur J Med Chem. 2013 July; 65:83-93). In November2013, Christoph, S. et al., published effects of a pyrazolopyrimidine(UNC569) in ALL and ATRT (atypical teratoid/rhabdoid tumors (ATRT)(“UNC569, a novel small-molecule Mer inhibitor with efficacy againstacute lymphoblastic leukemia in vitro and in vivo.” Mol Cancer Ther.2013 November; 12(11):2367-77). The MerTK inhibitors UNC569 and UNC1062have the following structures:

An important observation was made in 2013 that MerTK −/− knock-out miceare less susceptible to tumor growth than normal mice. MerTK is normallyexpressed in myeloid lineage cells where it acts to suppresspro-inflammatory cytokines following ingestion of apoptotic material. Itwas found that MerTK −/− leukocytes exhibit lower tumor cell-inducedexpression of wound healing cytokines (IL-10 and GAS6) and enhancedexpression of acute inflammatory cytokines (IL-12 and IL-6). Further,intratumoral CD8+ lymphocytes are increased. The loss of MerTK in thetumor microenvironment in Mer−/− mice slowed the establishment, growth,and metastasis of mammary tumors and melanomas in immune competent,syngeneic mice. Cook, R. S. et al., MerTK inhibition in tumor leukocytesdecreases tumor growth and metastasis, J Clin Invest 123, 3231-3242(2013).

Linger et al. have also presented data demonstrating increased MerTKexpression in E2A-PBX11 and other cytogenetic subgroups of B-acutelymphoblastic leukemia (B-ALL), and that MerTK inhibition may attenuateprosurvival and proliferation signaling Linger et al., Mer receptortyrosine kinase is a therapeutic target in pre-B-cell acutelymphoblastic leukemia, Blood, vol. 122(9):1599-1609, 2013. Lee-Sherick,et al. (“Efficacy of a Mer and Flt3 tyrosine kinase small moleculeinhibitor, UNC1666, in acute myeloid leukemia”, Oncotarget, AdvancePublications 2015 Feb. 10, 2015) have reported that UNC 1666 (apyrrolopyrimidine) decreases oncogenic signaling and myeloid survival inAML.

TAM (Tyro3-Axl-Mer) receptor tyrosine kinases have also beeninvestigated for their involvement in platelet aggregation. In 2004,Chen et al, from the Johnson & Johnson Pharmaceutical Research andDevelopment, published that MerTK, presumably through activation by itsligand Gas6, participates in the regulation of platelet function invitro and platelet-dependent thrombosis in vivo. Chen, et al, “MerReceptor tyrosine Kinase Signaling Participates in Platelet Function”,Arterioscler. Thromv. Vase. Biol. 1118-1123 June 2004. Chen reportedthat PtdSer on aggregating platelets activates MerTK, helping tostabilize clot formation. MerTK knockout mice have decreased plateletaggregation while maintaining normal bleeding times and coagulationparameters. Consequently, these mice appear to be protected fromthrombosis without concomitant increased spontaneous bleeding (see alsoAngelillo-Scherrer A et al., Role of Gas6 receptors in plateletsignaling during thrombus stabilization and implications forantithrombotic therapy. J. Clin. Invest. 2005, 115 (2), 237-246).

In 2007, Sather, et al., reported that membrane-bound MerTK is cleavedin the extracellular domain via a metalloproteinase to produce a solubleMerTK that decreased platelet aggregation in vitro and prevented fatalcollagen/epinephrine-induced thromboembolism. “A soluble form of the Merreceptor tyrosine kinase inhibits macrophage clearance of apoptoticcells and platelet aggregation”, Blood, Vol 109(3): 1026-1033).

Paolino et al. have reported on the treatment of wild-type NK cells witha newly developed small molecule TAM kinase inhibitor, LDC 1267, thatconferred therapeutic potential and efficiently enhancinganti-metastatic NK cell activity in vivo. Oral or intraperitonealadministration using this TAM inhibitor markedly reduced murine mammarycancer and melanoma metastases dependent on NK cells. See, Paolino, M.,et al., The E3 ligase Cbl-b and TAM receptors regulate cancer metastasisvia natural killer cells, Nature, vol. 507:508-512, 2014. LDC1267 is ahighly selective TAM kinase inhibitor with IC₅₀ of <5 nM, 8 nM, and 29nM for MerTK, Tyro3, and Axl, respectively, and has the chemicalstructure:

Bernsmeier, et al., have noted that characteristics of decompensatedcirrhosis and acute-on-chronic liver failure (ACLF) includesusceptibility to infection, immune paresis and monocyte dysfunction.The authors found that the number of monocytes and macrophages thatexpressed MerTK was greatly increased in circulation, livers and lymphnodes of patients with ACLF. They found that addition of a substitutedpyrazolopyrimidine UNC569 (see WO 2011/146313 filed by Wang, et al., andassigned to University of North Carolina at Chapel Hill, page 25)restored production of inflammatory cytokines. Bernsmeier, et al.,“Patients with Acute-on-Chronic Liver Failure Have Increased Numbers ofRegulatory Immune Cells Expressing the Receptor Tyrosine Kinase MERTK”,Gastroenterology 2015; 1-13.

It is an object of the invention to identify new methods andcompositions for the treatment of infectious diseases.

It is another object of the invention to identify new methods andcompositions for the treatment of thrombosis.

It is another object of the invention to identify new methods andcompositions for the treatment of a tumor, cancer or other neoplasm.

It is yet another object of the invention to identify new methods andcompositions for the treatment of disorders that can be treated withimmunosuppression, or which would benefit from immunostimulatorytherapy.

SUMMARY OF THE INVENTION

The present invention is directed to the use of selectedpyrazolopyrimidine compounds having Mer tyrosine kinase (MerTK)inhibitory activity as anti-infective agents, immunostimulatory agents,anti-cancer agents (including against MerTK −/− tumors and ITD and TKDmutant forms of Acute Myeloid Leukemia (AML)), and as adjunctive agentsin combination with chemotherapeutic, radiation or other standard ofcare for neoplasms.

An effective amount of the pyrazolopyrimidine compounds described inFormulas I, II, III, and IV below or other active compounds as otherwiseprovided herein can be used to treat a host bearing any virus-relatedinfection where the virus has a virion envelope phosphatidyl serine thatcomplexes with MerTK to achieve viral entry or is otherwise facilitatedby MerTK in the infectious process. Nonlimiting examples of such virusesinclude, but are not limited to, Flaviviridae viruses, includingFlavivirus (such as Yellow Fever, West Nile and Dengue), Hepacivirus(Hepatitis C virus, “HCV”), Pegivirus and Pestivirus (Bovine viraldiarrhea virus); Filoviridae viruses, including Ebola viruses;Togaviridae viruses, including Chikungunya virus; Coronaviruses, such asSARS (Severe acute respiratory syndrome) and MERS (Middle Eastrespiratory syndrome); Orthomyxoviridae viruses, for example influenza;Paramyxoviridae viruses, for example Respiratory syncytial virus (RSV),measles and mumps; and Caliciviridae viruses, including Lagovirus,Vesivirus, and Sapovirus and Norovirus (Norwalk-like virus), andLentiviruses, for example, HIV. In one embodiment, the virus is anenveloped virus. In another embodiment, the virus is a non-envelopedvirus. In one embodiment, the compound administered is UNC2207A.

It has also been discovered that an effective amount of thepyrazolopyrimidine compounds described in Formulas I, II, III, or IV canbe used to treat a host bearing a bacterial infection. In oneembodiment, the bacteria treated is, for example, a Gram-negativebacilli (GNB), especially Escherichia coli, Gram-positive cocci (GPC),Staphylococcus aureus, Enterococcus faecalis, or Streptococcuspneumoniae. In one embodiment, the bacterial infection is associatedwith liver failure. In one embodiment, an active compound disclosedherein is administered in combination with an antibiotic or anotheranti-bacterial agent. In one embodiment, the compound administered isUNC2207A.

It has also been discovered that the compounds described herein can beused as immunomodulatory agents that reverse the MerTK-inducedsuppression of pro-inflammatory cytokines such as wound healingcytokines (IL-10 and GAS6) and enhance the expression of acuteinflammatory cytokines (IL-12 and IL-6). In this way, thepyrazolopyrimidine compounds can “re-normalize” or “re-program” the hostmicroenvironment in the diseased tissue area to attack the diseasedcells.

Taking advantage of the immunostimulatory activity of the compoundsdescribed herein, or a pharmaceutically acceptable composition, salt,isotopic analog, or prodrug thereof, may be used for the treatment of aMERTK-negative (−/−) tumor or cancer, for example MERTK-negative (−/−)breast cancer.

As part of the invention, one or more of the compounds disclosed hereincan be used as adjunctive antineoplastic therapy for itsimmunostimulatory effect as a means to increase the efficacy of theantineoplastic standard of care therapies, such as chemotherapeuticcompounds or radiation.

Some of these pyrazolopyrimidine compounds have dual Mer/Flt-3inhibitory activity, as discussed in more detail below, and thus areuseful in the treatment of tumors mediated by FLT-3 or which exhibitdrug resistance or ITD and TKD mutations, such as certain forms of AcuteMyeloid Leukemia (AML)).

The compounds described as useful in the present inventions were firstdescribed in WO 2011/146313 and WO 2014/062774, which are incorporatedby reference for all purposes. The present invention describes for thefirst time that these compounds are useful for medical applications notdescribed in or flowing from these earlier published applications.Specifically, MerTK inhibitors useful in treating a disorder describedherein have the structure of Formula I or Formula II:

wherein:

R¹ is aryl such as phenyl (in some embodiments substituted 1, 2 or 3times with heterocycloalkylalkyl, which heterocycloalkylalkyl issubstituted or unsubstituted, for example substituted from 1 to 3 timeswith halo, or alkyl). In some embodiments, heterocycloalkylalkyl is asubstituent of the formula —R′R″, where R′ is substituted orunsubstituted C1-C2 alkyl, and R″ is a heterocyclo group, such as anoptionally substituted piperazine or morpholine group.

R² is —R⁵R⁶, where R⁵ is a covalent bond or C₁ to C₃ alkyl and R⁶ iscycloalkyl, heterocycloalkyl, aryl, heteroaryl or alkyl, and wherein R⁶is optionally substituted from one to two times with independentlyselected polar groups;

R³ is —NR⁷R⁸, where R⁷ and R⁸ are each independently selected from H,alkyl, arylalkyl, and alkoxyalkyl (typically one of R⁷ or R⁸ is H); and

R⁴ is H, loweralkyl, halo, or loweralkoxy;

-   -   or a pharmaceutically acceptable composition, salt, isotopic        analog, or prodrug thereof;

or

wherein:

R¹¹ is —R⁹(R¹⁰)_(n), where R⁹ is alkyl, alkenyl, -alkylaryl,heterocyclo, aryl, heteroaryl and R¹⁰ is hydrogen, alkyl, haloalkyl,alkoxyalkyl, —O-alkylaryl, hydroxyalkyl, alkenyl, alkenyloxy, alkynyl,alkynyloxy, cycloalkyl, cycloalkylalkyl, cycloalkoxy,cycloalkylalkyloxy, heterocyclo, heterocycloalkyl,alkylheterocycloalkyl, heterocyclooxy, heterocyclolalkyloxy, aryl,arylalkyl, aryloxy, arylalkyloxy, heteroaryl, alkylheteroaryl, halo,hydroxyl, alkoxy, haloalkoxy, mercapto, alkyl-S(O)_(m)—,haloalkyl-S(O)_(m)—, alkenyl-S(O)_(m)—, alkynyl-S(O)_(m)—,cycloalkyl-S(O)_(m)—, cycloalkylalkyl-S(O)_(m)—, aryl-S(O)_(m)—,arylalkyl-S(O)_(m)—, heterocyclo-S(O)_(m)—, heterocycloalkyl-S(O)_(m)—,amino, carboxy, alkylamino, —(CH₂)_(m)—NHalkyl, —(CH₂)_(m)—N(alkyl)₂,—(CH₂)_(m)—NH(CH₂)_(m)OH, —(CH₂)_(m)—NH(CH₂)_(m)cycloalkyl,—(CH₂)_(m)—NH(CH₂)₂₋₃heterocyclo, —(CH₂)_(m)—NH(CH₂)_(m)aryl,—(CH₂)_(m)—NH(CH₂)₂₋₃heteroaryl, —(CH₂)_(m)NH(CH₂)₂₋₃N(alkyl)₂,alkenylamino, alkynylamino, haloalkylamino, cycloalkylamino,cycloalkylalkylamino, arylamino, arylalkylamino, heterocycloamino,heterocycloalkylamino, disubstitutedamino, acylamino, acyloxy, ester,amide, S(O)₂OR²², CONHNH₂, cyano, nitro, aminosulfonyl, COOH,sulfonamide, urea, alkoxyacylamino, aminoacyloxy, —C(CH₂)₂R²², andwherein R¹⁰ is optionally substituted one, two or three times;

m=0, 1, 2 or 3;

n=0, 1 or 2;

R¹² is —R¹⁵R¹⁶ where R¹⁵ is a covalent bond or C₁ to C₃ alkyl and R¹⁶ iscycloalkyl, cycloalkylalkyl, heterocyclo, heterocycloalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl hydroxyalkyl, alkoxyalkyl, oralkyl, and wherein R¹⁶ is optionally substituted one, two or threetimes;

R¹³ is NR¹⁷R¹⁸, where;

R¹⁷ is selected from the group consisting of H, alkyl, haloalkyl,hydroxyalkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclo,heterocycloalkyl, alkylheterocycloalkyl, heteroaryl, heteroarylalkyl,and alkoxyalkyl, each of which is optionally substituted one, two orthree times (typically R¹⁷ is H);

R¹⁸ is selected from the group consisting of H, alkyl, haloalkyl,hydroxyalkyl, aryl, arylalkyl; cycloalkyl, cycloalkylalkyl, heterocyclo,heterocycloalkyl, alkylheterocycloalkyl, heteroaryl, heteroarylalkyl,and alkoxyalkyl, each of which is optionally substituted one, two orthree times; or

R¹⁷ and R¹⁸ together with the nitrogen to which they are bonded can forma heterocyclic group that can be optionally substituted;

R¹⁴ is H, loweralkyl, halo, or loweralkoxy;

R²² is selected from alkyl, alkenyl, alkynyl, aryl, arylalkyl,cycloalkyl, cycloalkylalkyl, heterocyclo, heterocycloalkyl, heteroaryl,or heteroarylalkyl;

or a pharmaceutically acceptable composition, salt, isotopic analog, orprodrug thereof.

A further embodiment of the invention is a compound of Formula I, and IIas described herein in a pharmaceutically acceptable carrier.

The present invention provides at least the following:

-   -   (a) Use of a compound of Formula I, II, III, or IV, as described        herein, and pharmaceutically acceptable compositions, salts,        isotopic analogs, or prodrugs thereof, to treat a host with an        thrombotic or clotting disorder. In one embodiment, the compound        is selected from the compounds described in Tables 1 and 2, or a        pharmaceutically acceptable composition, salt, isotopic analog        or prodrug thereof. In one embodiment, the MerTK inhibitory        compound administered is UNC2207A.    -   (b) Use of a compound of Formula I, II, III, or IV, as described        herein, and pharmaceutically acceptable compositions, salts,        isotopic analogs, or prodrugs thereof, for the treatment or        prevention of a viral or bacterial infection. In one embodiment,        the compound is selected from the compounds described in Tables        1 and 2, or a pharmaceutically acceptable composition, salt,        isotopic analog or prodrug thereof. In one embodiment, the MerTK        inhibitory compound administered is UNC2207A.    -   (c) Use of a compound of Formula I, II, III, or IV, as described        herein, and pharmaceutically acceptable compositions, salts,        isotopic analogs, or prodrugs thereof, to treat a host with a        selected cancer. In one embodiment, the compound is selected        from the compounds described in Tables 1 and 2, or a        pharmaceutically acceptable composition, salt, isotopic analog        or prodrug thereof. In one embodiment, the MerTK inhibitory        compound administered is UNC2207A.    -   (d) Use of a compound of Formula I, II, III, or IV, as described        herein, and pharmaceutically acceptable salts and prodrugs        thereof, to treat a host with acute myeloid leukemia (including        FLT3-ITD AML, FLT3-TKD AML, or AML having both FLT3-ITD and        FLT3-TKD mutations). In one embodiment, the compound is selected        from the compounds described in Tables 1 and 2, or a        pharmaceutically acceptable composition, salt, isotopic analog        or prodrug thereof. In one embodiment, the MerTK inhibitory        compound administered is UNC2207A.    -   (e) Use of a compound of Formula I, II, III, or IV, as described        herein, and pharmaceutically acceptable compositions, salts,        isotopic analogs, or prodrugs thereof, to treat a host having a        cancer as an immunomodulatory agent to inhibit Mer tyrosine        kinase activity in a tumor associated macrophage in order to        suppress tumor immunity. In one embodiment, a method for the        treatment of a cancer is provided that includes administering an        effective amount of a Mer TKI to inhibit TK signaling in a tumor        associated macrophage. In one embodiment, the cancer is a        MERTK-negative (−/−) cancer. In one embodiment, the cancer is a        MERTK-negative (−/−) breast cancer. In one embodiment, the        compound is selected from the compounds described in Tables 1        and 2, or a pharmaceutically acceptable composition, salt,        isotopic analog or prodrug thereof. In one embodiment, the MerTK        inhibitory compound administered is UNC2207A.    -   (f) A compound selected from the group consisting of UNC2207A        and pharmaceutically acceptable compositions, salts, isotopic        analogs, and prodrugs thereof    -   (g) Use of a compound of Formula I, II, III, or IV, as described        herein, and pharmaceutically acceptable compositions, salts,        isotopic analogs, or prodrugs thereof, optionally in a        pharmaceutical composition, to treat a host, typically a human,        with a selected cancer, thrombotic or clotting disorder, or        viral or bacterial infection, wherein the compound is selected        from the group consisting of UNC2207A.    -   (h) A compound of Formula I, II, III, or IV, and        pharmaceutically acceptable salts and prodrugs thereof for use        in the manufacture of a medicament for use in treating cancer,        modulating the immune system, treating a thrombotic or clotting        disorder, or treating or preventing a viral or bacterial        infection.    -   (i) A process for manufacturing a medicament intended for the        therapeutic use of treating cancer, modulating the immune        system, treating a thrombotic or clotting disorder, or treating        or preventing a viral or bacterial infection, characterized in        that Formula I, II, III, or IV as described herein is used in        the manufacture.

BRIEF DESCRIPTION OF FIGURES

FIG. 1A illustrates the Ig-like domain, FNIII domain and kinase domainin Tyro-3, Axl and MerTK. FIG. 1B illustrates the Gla domain, EGFrepeat, LG1 domain and LG2 domain in MerTK. The Gas6/protein S loopregion is also illustrated. FIG. 1C and FIG. 1D are scanning EMillustrates the binding of apoptotic thymocytes to MerTK^(+/+) andMerTK^(−/−) macrophages. Wild-type macrophages ingest; MerTK^(−/−) donot.

FIG. 2A illustrates the results obtained when MMTV-PVmT mammary tumorswere implanted into MerTK^(+/−), MerTK^(+/+) and MerTK^(−/−) mice.Tumors that were implanted into MerTK^(−/−) mice were almost 75% tumorfree after 200 days. FIG. 2B illustrates the results when B16:F10intradermal tumors were implanted in MerTK^(+/+) or MerTK^(−/−) mice.MerTK^(−/−) mice were tumor free for 40 days and MerTK^(+/+) mice weretumor free for approximately 28 days. FIG. 2C is a graph showing thenumber of lung metastases per mouse verses the genotype of micetransplanted with MMTV-PvVmT or B16:F10 tumor lines.

FIG. 3: MerTK is a dual target in cancer. MerTK is over expressed intumor cells such as lung, melanoma and GBM and sends a survival signal.MerTK inhibitors inhibit tumor cell survival and chemoresistance. Inaddition, MerTK is expressed in tumor-associated macrophages (e.g.,breast, melanoma and lung cancer) and suppresses tumor immunity. MerTKinhibitors stimulate innate anti-tumor immunity.

FIG. 4 is a graph illustrating percent change in melanoma tumor volumein a genetically-engineered mouse (GEM) model (TRIA) after 21 days oftreatment with various drugs and combinations of drugs. MEK plus P13K(AZD6244/BEZ235) was the only regimen to show efficacy in the model.This combination is not tolerated in humans.

FIG. 5A is a graph illustrating relative levels of MerTK proteinexpression (AQUA score (log 2) determined by immunohistochemistry innevus, primary melanoma, and metastatic melanoma samples. FIGS. 5B to 5Fshow reduced colony formation in soft agar in response to treatment withUNC 1062 in B-RAF wild type HMCB (A) and B-RAF mutant G361 (B) melanomacell lines. FIG. 5G shows reduced invasion into collagen matrix bySKMEL119 melanoma cells in response to treatment with UNC1062.

FIG. 6A illustrates a Mer_(tg) spleen verses a wild type spleen. FIG. 6Billustrates an enlarged Mer_(tg) lymph node. FIG. 6C is a picture ofcells from a Mer_(tg) lymph node. FIG. 6D shows MerTK expression inpediatric ALL patients detected by RT-PCR. FIGS. 6E and 6F illustratethe percent of adult and pediatric patients with acute myeloid leukemiasthat are MerTK positive, MerTK Dim, or MerTK negative. See, Graham,Armistead et al., Oncogene, 2013.

FIG. 7A shows induction of apoptosis and cell death in cultures of theBRAF mutant G361 cell line treated with UNC1062, vemurafenib, or UNC1062and vemurafenib. In addition, the percent of apoptotic and dead cellsexpected if the interaction between UNC 1062 and vemurafenib is additivewas calculated using the Bliss additivity model (Additive Fa). Thepercent apoptotic and dead cells observed (Actual Fa) was greater thanthe predicted additive value, indicating a synergistic interaction. FIG.7B shows inhibition of signaling downstream of BRAF and/or MerTK inresponse to treatment with UNC1062, vemurafenib, or UNC1062 andvemurafenib.

FIG. 8 shows the chemical structure of UNC 1062.

DETAILED DESCRIPTION 1. Terminology

Compounds are described using standard nomenclature. Unless definedotherwise, all technical and scientific terms used herein have the samemeaning as is commonly understood by one of skill in the art to whichthis invention belongs.

The compounds in any of the Formulas described herein includeenantiomers, mixtures of enantiomers, diastereomers, tautomers,racemates and other isomers, such as rotamers, as if each isspecifically described.

The terms “a” and “an” do not denote a limitation of quantity, butrather denote the presence of at least one of the referenced item. Theterm “or” means “and/or”. Recitation of ranges of values are merelyintended to serve as a shorthand method of referring individually toeach separate value falling within the range, unless otherwise indicatedherein, and each separate value is incorporated into the specificationas if it were individually recited herein. The endpoints of all rangesare included within the range and independently combinable. All methodsdescribed herein can be performed in a suitable order unless otherwiseindicated herein or otherwise clearly contradicted by context. The useof examples, or exemplary language (e.g., “such as”), is intended merelyto better illustrate the invention and does not pose a limitation on thescope of the invention unless otherwise claimed.

In one embodiment, the present invention includes compounds of FormulaI, II, III, or IV, and the use of compounds with at least one desiredisotopic substitution of an atom, at an amount above the naturalabundance of the isotope, i.e., enriched. Isotopes are atoms having thesame atomic number but different mass numbers, i.e., the same number ofprotons but a different number of neutrons.

Examples of isotopes that can be incorporated into compounds of theinvention include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorous, fluorine, and chlorine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N,¹⁸F ³¹P, ³²P, ³⁵S, ³⁶CI, ¹²⁵I respectively. The invention includesvarious isotopically labeled compounds as defined herein, for examplethose into which radioactive isotopes, such as ³H, ¹³C, and ¹⁴C, arepresent. Such isotopically labelled compounds are useful in metabolicstudies (with ¹⁴C), reaction kinetic studies (with, for example ²H or³H), detection or imaging techniques, such as positron emissiontomography (PET) or single-photon emission computed tomography (SPECT)including drug or substrate tissue distribution assays, or inradioactive treatment of patients. In particular, an ¹⁸F labeledcompound may be particularly desirable for PET or SPECT studies.Isotopically labeled compounds of this invention and prodrugs thereofcan generally be prepared by carrying out the procedures disclosed inthe schemes or in the examples and preparations described below bysubstituting a readily available isotopically labeled reagent for anon-isotopically labeled reagent.

By way of general example and without limitation, isotopes of hydrogen,for example, deuterium (²H) and tritium (³H) may be used anywhere indescribed structures. Alternatively or in addition, isotopes of carbon,e.g., ¹³C and ¹⁴C, may be used. A typical isotopic substitution isdeuterium for hydrogen at one or more locations on the molecule toimprove the performance of the drug, for example, the pharmacodynamics,pharmacokinetics, biodistribution, half-life, stability, AUC, Tmax,Cmax, etc. For example, the deuterium can be bound to carbon in alocation of bond breakage during metabolism (an α-deuterium kineticisotope effect) or next to or near the site of bond breakage (aβ-deuterium kinetic isotope effect).

Isotopic substitutions, for example deuterium substitutions, can bepartial or complete. Partial deuterium substitution means that at leastone hydrogen is substituted with deuterium. In certain embodiments, theisotope is 90, 95 or 99% or more enriched in an isotope at any locationof interest. In one embodiments deuterium is 90, 95 or 99% enriched at adesired location. Unless otherwise stated, the enrichment at any pointis above natural abundance and enough to alter a detectable property ofthe drug in a human.

In one embodiment, the substitution of a hydrogen atom for a deuteriumatom occurs within an R group when at least one of the variables withinthe R group is hydrogen (e.g., ²H or D) or alkyl (e.g., CD₃). Forexample, when any of R groups are, or contain for example throughsubstitution, methyl or ethyl, the alkyl residue is typicallydeuterated, e.g., CD₃, CH₂CD₃ or CD₂CD₃. In certain other embodiments,when any of the above mentioned R groups are hydrogen, the hydrogen maybe isotopically enriched as deuterium (i.e., ²H).

A dash (“-”) that is not between two letters or symbols is used toindicate a point of attachment for a substituent. For example, —(C═O)NH₂is attached through carbon of the keto (C═O) group.

“Alkyl” as used herein alone or as part of another group, refers to astraight or branched chain hydrocarbon containing from 1 to 10 carbonatoms. In one embodiment, the alkyl contains from 1 to about 10 carbonatoms, more generally from 1 to about 6 carbon atoms or from 1 to about4 carbon atoms. In certain embodiments, the alkyl is C₁-C₃ or C₁-C₈. Thespecified ranges as used herein indicate an alkyl group having eachmember of the range described as an independent species. For example,the term C₁-C₃ alkyl as used herein indicates a straight or branchedalkyl group having from 1, 2, or 3 carbon atoms and is intended to meanthat each of these is described as an independent species. For example,the term C₁-C₃alkyl as used herein indicates a straight or branchedalkyl group having from 1, 2, or 3 carbon atoms and is intended to meanthat each of these is described as an independent species.Representative examples of alkyl include, but are not limited to,methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl,tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl,2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl,n-decyl, and the like. “Lower alkyl” as used herein, is a subset ofalkyl, in some embodiments typically, and refers to a straight orbranched chain hydrocarbon group containing from 1 to 4 carbon atoms.Representative examples of lower alkyl include, but are not limited to,methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, andthe like. The term “alkyl” or “loweralkyl” is intended to include bothsubstituted and unsubstituted alkyl or loweralkyl unless otherwiseindicated and these groups may be substituted with groups selected fromhalo (e.g., haloalkyl), alkyl, haloalkyl, hydroxyalkyl, alkenyl,alkynyl, cycloalkyl (including spiroalkyl, e.g., —C(CH₂)₂₋₄ spiroalkyl),cycloalkylalkyl, aryl, arylalkyl, heterocyclo, heterocycloalkyl,alkylheterocycloalkyl, heteroaryl, alkylheteroaryl, hydroxyl, alkoxy(thereby creating a polyalkoxy such as polyethylene glycol), alkenyloxy,alkynyloxy, haloalkoxy, cycloalkoxy, cycloalkylalkyloxy, aryloxy,arylalkyloxy, heterocyclooxy, heterocyclolalkyloxy, mercapto,alkyl-S(O)_(m), haloalkyl-S(O)_(m), alkenyl-S(O)_(m), alkynyl-S(O)_(m),cycloalkyl-S(O)_(m), cycloalkylalkyl-S(O)_(m), aryl-S(O)_(m),arylalkyl-S(O)_(m), heterocyclo-S(O)_(m), heterocycloalkyl-S(O)_(m),amino, carboxy, alkylamino, —(CH₂)_(m)—NH(CH₂)_(m)CH₃,—(CH₂)_(m)—NH(CH₂)_(m)OH, alkenylamino, alkynylamino, haloalkylamino,cycloalkylamino, cycloalkylalkylamino, arylamino, arylalkylamino,heterocycloamino, heterocycloalkylamino, disubstituted-amino, acylamino,acyloxy, ester, amide, sulfonamide, urea, alkoxyacylamino, aminoacyloxy,nitro or cyano where m=0, 1, 2 or 3. In one embodiment, alkyl orloweralkyl can be substituted with groups selected from a polar group,—(CH₂)_(m)—N(R⁵⁰)₂, —(CH₂)_(m)—NH(CH₂)_(m)R⁵⁰,—(CH₂)_(m)NH(CH₂)₂₋₃N(R⁵⁰)₂, —S(O)₂OR⁵⁰, —CONHNHR⁵⁰, aminosulfonyl—C(CH₂)₂R⁵⁰ wherein each R⁵⁰ is independently selected from hydrogen,alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl,heterocyclo, heterocycloalkyl, heteroaryl, or heteroarylalkyl.

“Alkenyl” as used herein alone or as part of another group, refers to astraight or branched chain hydrocarbon containing from 1 to 10 carbonatoms (or in loweralkenyl 1 to 4 carbon atoms) which include 1 to 4double bonds in the normal chain. Representative examples of alkenylinclude, but are not limited to, vinyl, 2-propenyl, 3-butenyl,2-butenyl, 4-pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl, 2,4-heptadiene,and the like. The term “alkenyl” or “loweralkenyl” is intended toinclude both substituted and unsubstituted alkenyl or loweralkenylunless otherwise indicated and these groups may be substituted withgroups as described in connection with alkyl and loweralkyl above.

“Alkynyl” as used herein alone or as part of another group, refers to astraight or branched chain hydrocarbon containing from 1 to 10 carbonatoms (or in loweralkynyl 1 to 4 carbon atoms) which include 1 triplebond in the normal chain. Representative examples of alkynyl include,but are not limited to, 2-propynyl, 3-butynyl, 2-butynyl, 4-pentynyl,3-pentynyl, and the like. The term “alkynyl” or “loweralkynyl” isintended to include both substituted and unsubstituted alkynyl orloweralkynyl unless otherwise indicated and these groups may besubstituted with the same groups as set forth in connection with alkyland loweralkyl above.

“Cycloalkyl” as used herein alone or as part of another group, refers toa saturated or partially unsaturated cyclic hydrocarbon group containingfrom 3, 4 or 5 to 6, 7 or 8 carbons (which carbons may be replaced in aheterocyclic group as discussed below). Representative examples ofcycloalkyl include, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, and cyclooctyl. These rings may be optionally substitutedwith additional substituents as described herein such as halo orloweralkyl. The term “cycloalkyl” is generic and intended to includeheterocyclic groups as discussed below unless specified otherwise. Inone embodiment, as used herein, the term “cycloalkyl” refers to asaturated or unsaturated hydrocarbon mono- or multi-ring, e.g., fused,bridged, or Spiro rings system having 3 to 15 carbon atoms (e.g.,C₃-C₁₀). Examples of cycloalkyl include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, and adamantyl. In another embodiment, the term “cycloalkyl”refers to a saturated or partially unsaturated, monocyclic, fusedbicyclic or bridged polycyclic ring assembly containing from 3 to 12ring atoms, or the number of atoms indicated. Cycloalkyl can include anynumber of carbons, such as C₃₋₆, C₄₋₆, C₅₋₆, C₃₋₈, C₄₋₈, C₅₋₈, and C₆₋₈.Saturated monocyclic cycloalkyl rings include, for example, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. Saturated bicyclicand polycyclic cycloalkyl rings include, for example, norbornane,[2.2.2]bicyclooctane, decahydronaphthalene and adamantane. Cycloalkylgroups can also be partially unsaturated, having one or more doublebonds in the ring. Representative cycloalkyl groups that are partiallyunsaturated include, but are not limited to, cyclobutene, cyclopentene,cyclohexene, cyclohexadiene (1,3- and 1,4-isomers), cycloheptene,cycloheptadiene, cyclooctene, cyclooctadiene (1,3-, 1,4- and1,5-isomers), norbornene, and norbornadiene. These groups may besubstituted with groups as described in connection with alkyl andloweralkyl above.

“Heterocyclic group” or “heterocyclo” as used herein alone or as part ofanother group, refers to an aliphatic (e.g., fully or partiallysaturated heterocyclo) or aromatic (e.g., heteroaryl)monocyclic- or abicyclic-ring system. In some embodiments, monocyclic ring systems areexemplified by any 7 membered ring containing 1, 2, 3, or 4 heteroatomsindependently selected from oxygen, nitrogen and sulfur. Monocyclic ringsystems are exemplified by any 5 or 6 membered ring containing 1, 2, 3,or 4 heteroatoms independently selected from oxygen, nitrogen andsulfur. The 5 membered ring has from 0-2 double bonds and the 6 memberedring has from 0-3 double bonds. Representative examples of monocyclicring systems include, but are not limited to, azetidine, azepine,aziridine, diazepine, 1,3-dioxolane, dioxane, dithiane, furan,imidazole, imidazoline, imidazolidine, isothiazole, isothiazoline,isothiazolidine, isoxazole, isoxazoline, isoxazolidine, morpholine,oxadiazole, oxadiazoline, oxadiazolidine, oxazole, oxazoline,oxazolidine, piperazine, piperidine, pyran, pyrazine, pyrazole,pyrazoline, pyrazolidine, pyridine, pyrimidine, pyridazine, pyrrole,pyrroline, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, tetrazine,tetrazole, thiadiazole, thiadiazoline, thiadiazolidine, thiazole,thiazoline, thiazolidine, thiophene, thiomorpholine, thiomorpholinesulfone, thiopyran, triazine, triazole, trithiane, and the like.Bicyclic ring systems are exemplified by any of the above monocyclicring systems fused to an aryl group as defined herein, a cycloalkylgroup as defined herein, or another monocyclic ring system as definedherein. Representative examples of bicyclic ring systems include but arenot limited to, for example, benzimidazole, benzothiazole,benzothiadiazole, benzothiophene, benzoxadiazole, benzoxazole,benzofuran, benzopyran, benzothiopyran, benzodioxine, 1,3-benzodioxole,cinnoline, indazole, indole, indoline, indolizine, naphthyridine,isobenzofuran, isobenzothiophene, isoindole, isoindoline, isoquinoline,phthalazine, purine, pyranopyridine, quinoline, quinolizine,quinoxaline, quinazoline, tetrahydroisoquinoline, tetrahydroquinoline,thiopyranopyridine, and the like. These rings include quaternizedderivatives thereof and may be optionally substituted with groupsselected from halo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, aryl, arylalkyl, heterocyclo, heterocycloalkyl,hydroxyl, alkoxy, alkenyloxy, alkynyloxy, haloalkoxy, cycloalkoxy,cycloalkylalkyloxy, aryloxy, arylalkyloxy, heterocyclooxy,heterocyclolalkyloxy, mercapto, alkyl-S(O)_(m), haloalkyl-S(O)_(m),alkenyl-S(O)_(m), alkynyl-S(O)_(m), cycloalkyl-S(O)_(m),cycloalkylalkyl-S(O)_(m), aryl-S(O)_(m), arylalkyl-S(O)_(m),heterocyclo-S(O)_(m), heterocycloalkyl-S(O)_(m), amino, alkylamino,—(CH₂)_(m)—NH(CH₂)_(m)CH₃, —(CH₂)_(m)—NH(CH₂)_(m)OH alkenylamino,alkynylamino, haloalkylamino, cycloalkylamino, cycloalkylalkylamino,arylamino, arylalkylamino, heterocycloamino, heterocycloalkylamino,disubstituted-amino, acylamino, acyloxy, ester, amide, sulfonamide,urea, alkoxyacylamino, aminoacyloxy, nitro or cyano where m=0, 1, 2 or3. In some embodiments, the heterocyclo groups can be substituted withgroups as described in connection with alkyl and loweralkyl above. Inanother embodiment, the term “heterocyclo” refers to a saturated orunsaturated nonaromatic 3-8 membered monocyclic, 7-12 membered bicyclic(fused, bridged, or spiro rings), or 11-14 membered tricyclic ringsystem (fused, bridged, or Spiro rings) having one or more heteroatoms(such as O, N, or S), unless specified otherwise. Examples ofheterocyclo groups include, but are not limited to, piperidinyl,piperazinyl, pyrrolidinyl, dioxanyl, tetrahydrofuranyl, isoindolinyl,indolinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl,triazolidinyl, tetrahyrofuranyl, oxiranyl, azetidinyl, oxetanyl,thietanyl, 1,2,3,6-tetrahydropyridinyl, tetrahydropyranyl,dihydropyranyl, pyranyl, morpholinyl, 1,4-diazepanyl, 1,4-oxazepanyl,2-oxa-5-azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl,2-oxa-6-azaspiro[3.3]heptanyl, 2,6-diazaspiro[3.3]heptanyl,1,4-dioxa-8-azaspiro[4.5]decanyl and the like. These groups may besubstituted with groups as described in connection with alkyl andloweralkyl above.

“Aryl” as used herein alone or as part of another group, refers to amonocyclic carbocyclic ring system or a bicyclic carbocyclic fused ringsystem having one or more aromatic rings. Representative examples ofaryl include, azulenyl, indanyl, indenyl, naphthyl, phenyl,tetrahydronaphthyl, and the like. The term “aryl” is intended to includeboth substituted and unsubstituted aryl unless otherwise indicated andthese groups may be substituted with the same groups as set forth inconnection with alkyl and loweralkyl above.

“Arylalkyl” as used herein alone or as part of another group, refers toan aryl group, as defined herein, appended to the parent molecularmoiety through an alkyl group, as defined herein. Representativeexamples of arylalkyl include, but are not limited to, benzyl,2-phenylethyl, 3-phenylpropyl, 2-naphth-2-ylethyl, and the like.

“Heteroaryl” as used herein is as described in connection withheterocyclo above.

“Alkoxy” as used herein alone or as part of another group, refers to analkyl or loweralkyl group, as defined herein (and thus includingsubstituted versions such as polyalkoxy), appended to the parentmolecular moiety through an oxy group, —O—. Representative examples ofalkoxy include, but are not limited to, methoxy, ethoxy, propoxy,2-propoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy and the like.

“Halo” as used herein refers to any suitable halogen, including —F, —Cl,—Br, and —I.

“Mercapto” as used herein refers to an —SH group.

“Azido” as used herein refers to an —N₃ group.

“Cyano” as used herein refers to a —CN group.

“Formyl” as used herein refers to a —C(O)H group.

“Carboxylic acid” as used herein refers to a —C(O)OH group.

“Hydroxyl” as used herein refers to an —OH group.

“Nitro” as used herein refers to an —NO₂ group.

“Acyl” as used herein alone or as part of another group refers to a—C(O)R radical, where R is any suitable substituent such as aryl, alkyl,alkenyl, alkynyl, cycloalkyl or other suitable substituent as describedherein.

“Alkylthio” as used herein alone or as part of another group, refers toan alkyl group, as defined herein, appended to the parent molecularmoiety through a thio moiety, as defined herein. Representative examplesof alkylthio include, but are not limited, methylthio, ethylthio,tert-butylthio, hexylthio, and the like.

“Amino” as used herein means the radical —NH₂.

“Alkylamino” as used herein alone or as part of another group means theradical —NHR, where R is an alkyl group.

“Arylalkylamino” as used herein alone or as part of another group meansthe radical —NHR, where R is an arylalkyl group.

“Disubstituted-amino” as used herein alone or as part of another groupmeans the radical —NR_(a)R_(b), where R_(a) and R_(b) are independentlyselected from the groups hydrogen, alkyl, haloalkyl, alkenyl, alkynyl,cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclo,heterocycloalkyl.

“Acylamino” as used herein alone or as part of another group means theradical —NR_(a)R_(b), where R_(a) is an acyl group as defined herein andR_(b) is selected from the groups hydrogen, alkyl, haloalkyl, alkenyl,alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclo,heterocycloalkyl.

“Acyloxy” as used herein alone or as part of another group means theradical —OR, where R is an acyl group as defined herein.

“Ester” as used herein alone or as part of another group refers to a—C(O)OR radical, where R is any suitable substituent such as alkyl,cycloalkyl, alkenyl, alkynyl or aryl.

“Amide” as used herein alone or as part of another group refers to a—C(O)NR_(a)R_(b) radical, where R_(a) and R_(b) are any suitablesubstituent such as alkyl, cycloalkyl, alkenyl, alkynyl or aryl. In someembodiments, R_(a) and R_(b) together with the nitrogen to which theyare bonded form a heterocyclic ring.

“Sulfoxyl” as used herein refers to a compound of the formula —S(O)R,where R is any suitable substituent such as alkyl, cycloalkyl, alkenyl,alkynyl or aryl.

“Sulfonyl” as used herein refers to a compound of the formula —S(O)(O)R,where R is any suitable substituent such as amino, alkyl, cycloalkyl,alkenyl, alkynyl or aryl.

“Sulfonate” as used herein refers to a compound of the formula—S(O)(O)OR, where R is any suitable substituent such as alkyl,cycloalkyl, alkenyl, alkynyl or aryl.

“Sulfonic acid” as used herein refers to a compound of the formula—S(O)(O)OH.

“Sulfonamide” as used herein alone or as part of another group refers toa —S(O)₂NR_(a)R_(b) radical, where R_(a) and R_(b) are any suitablesubstituent such as H, alkyl, cycloalkyl, alkenyl, alkynyl or aryl. Insome embodiments, R_(a) and R_(b) are any suitable substituent such ashydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl,cycloalkylalkyl, heterocyclo, heterocycloalkyl, heteroaryl, orheteroarylalkyl and each R_(a) and R_(b) can be optionally substitutedone, two or three times. In some embodiments, R_(a) and R_(b) togetherwith the nitrogen to which they are bonded form a heterocyclic ring thatcan be optionally substituted one, two or three times.

“Urea” as used herein alone or as part of another group refers to an—N(R_(c))C(O)NR_(a)R_(b)radical, where R_(a), R_(b) and R_(c) are anysuitable substituent such as H, alkyl, cycloalkyl, alkenyl, alkynyl oraryl. In some embodiments, R_(a) and R_(b) together with the nitrogen towhich they are bonded form a heterocyclic ring.

“Alkoxyacylamino” as used herein alone or as part of another grouprefers to an —N(R_(a))C(O)OR_(b) radical, where R_(a), R_(b) are anysuitable substituent such as H, alkyl, cycloalkyl, alkenyl, alkynyl oraryl.

“Aminoacyloxy” as used herein alone or as part of another group refersto an —OC(O)NR_(a)R_(b) radical, where R_(a) and R_(b) are any suitablesubstituent such as H, alkyl, cycloalkyl, alkenyl, alkynyl or aryl. Insome embodiments, R_(a) and R_(b) together with the nitrogen to whichthey are bonded form a heterocyclic ring.

“Optionally substituted” as used herein refers to the optionallysubstitution of a chemical moiety. These moieties can be substitutedwith groups selected from, but not limited to, halo (e.g., haloalkyl),alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl (includingspiroalkyl, e.g., —C(CH₂)₂₋₄— spiroalkyl), cycloalkylalkyl, aryl,arylalkyl, aryl substituted heteroaryl, heterocyclo, heterocycloalkyl,alkylheterocycloalkyl, heteroaryl, heteroarylalkyl, hydroxyl, alkoxy(thereby creating a polyalkoxy such as polyethylene glycol), alkenyloxy,alkynyloxy, haloalkoxy, cycloalkoxy, cycloalkylalkyloxy, aryloxy,arylalkyloxy, heterocyclooxy, heterocyclolalkyloxy, mercapto,alkyl-S(O)_(m), haloalkyl-S(O)_(m), alkenyl-S(O)_(m), alkynyl-S(O)_(m),cycloalkyl-S(O)_(m), cycloalkylalkyl-S(O)_(m), aryl-S(O)_(m),arylalkyl-S(O)_(m), heterocyclo-S(O)_(m), heterocycloalkyl-S(O)_(m),amino, carboxy, alkylamino, —(CH₂)_(n)—NH(CH₂)_(m)CH₃,—(CH₂)_(m)—NH(CH₂)_(m)OH, alkenylamino, alkynylamino, haloalkylamino,cycloalkylamino, cycloalkylalkylamino, arylamino, arylalkylamino,heterocycloamino, heterocycloalkylamino, disubstituted-amino, acylamino,acyloxy, ester, amide, sulfonamide, urea, alkoxyacylamino, aminoacyloxy,nitro, polar group or cyano where m=0, 1, 2 or 3. In one embodiment,alkyl or loweralkyl can be substituted with groups selected from a polargroup, —(CH₂)_(m)—N(R⁵⁰)₂, —(CH₂)_(m)—NH(CH₂)_(m)R⁵⁰,—(CH₂)_(m)NH(CH₂)₂₋₃N(R⁵⁰)₂, —S(O)₂OR⁵⁰, —CONHNHR⁵⁰, aminosulfonyl—C(CH₂)₂R⁵⁰ wherein each R⁵⁰ is independently selected from hydrogen,alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl,heterocyclo, heterocycloalkyl, heteroaryl, or heteroarylalkyl.

“Polar group” as used herein refers to a group wherein the nuclei of theatoms covalently bound to each other to form the group do not share theelectrons of the covalent bond(s) joining them equally; that is theelectron cloud is denser about one atom than another. This results inone end of the covalent bond(s) being relatively negative and the otherend relatively positive; i.e., there is a negative pole and a positivepole. Examples of polar groups include, without limitations, halo,hydroxy, alkoxy, carboxy, nitro, cyano, amino (primary, secondary andtertiary), amido, ureido, sulfonamido, sulfinyl, sulfhydryl, silyl,S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, C-amido, N-amido,sulfonyl, N-tert-butoxycarbonyl (or “t-BOC”) groups, phosphono,morpholino, piperazinyl, tetrazolo, and the like. See, e.g., U.S. Pat.No. 6,878,733, as well as alcohol, thiol, polyethylene glycol, polyol(including sugar, aminosugar, uronic acid), sulfonamide, carboxamide,hydrazide, N-hydroxycarboxamide, urea, metal chelates (includingmacrocyclic ligand or crown ether metal chelates). The polar group canbe an ionic group.

“Ionic group” as used herein includes anionic and cationic groups, andincludes groups (sometimes referred to as “ionogenic” groups) that areuncharged in one form but can be easily converted to ionic groups (forexample, by protonation or deprotonation in aqueous solution). Examplesinclude but are not limited to carboxylate, sulfonate, phosphate, amine,N-oxide, and ammonium (including quaternized heterocyclic amines such asimidazolium and pyridinium) groups. See, e.g., U.S. Pat. Nos. 6,478,863;6,800,276; and 6,896,246. Additional examples include uronic acids,carboxylic acid, sulfonic acid, amine, and moieties such as guanidinium,phosphoric acid, phosphonic acid, phosphatidyl choline, phosphonium,borate, sulfate, etc.

“Deuterium” as used herein alone or as part of another group, refers to²H, which has one proton and one neutron in the nucleus. It is a safe,non-radioactive isotope of hydrogen. Any hydrogen in a group orsubstituent described above may be replaced with deuterium to provide a“deuterated” compound, in some embodiments to modify and/or improvemetabolic stability, resulting in better safety, tolerability and/orefficacy.

“Treat” as used herein refers to any type of treatment that imparts abenefit to a patient afflicted with a disease, including improvement inthe condition of the patient (e.g., in one or more symptoms), delay inthe progression of the disease, delay in onset of the disease, etc.

“Pharmaceutically acceptable” as used herein means that the compound orcomposition is suitable for administration to a subject to achieve thetreatments described herein, without unduly deleterious side effects inlight of the severity of the disease and necessity of the treatment.

A “dosage form” means a unit of administration of an active agent.Examples of dosage forms include tablets, capsules, injections,suspensions, liquids, emulsions, implants, particles, spheres, creams,ointments, suppositories, inhalable forms, transdermal forms, buccal,sublingual, topical, gel, mucosal, and the like.

“Pharmaceutical compositions” are compositions comprising at least oneactive agent, such as a compound or salt of Formula I, II, III, or IV,and at least one other substance, such as a carrier. “Pharmaceuticalcombinations” are combinations of at least two active agents which maybe combined in a single dosage form or provided together in separatedosage forms with instructions that the active agents are to be usedtogether to treat any disorder described herein.

“Pharmaceutically acceptable salts” includes derivatives of thedisclosed compounds in which the parent compound is modified by makinginorganic and organic, non-toxic, acid or base addition salts thereof.The salts of the present compounds can be synthesized from a parentcompound that contains a basic or acidic moiety by conventional chemicalmethods. Generally, such salts can be prepared by reacting free acidforms of these compounds with a stoichiometric amount of the appropriatebase (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, or thelike), or by reacting free base forms of these compounds with astoichiometric amount of the appropriate acid. Such reactions aretypically carried out in water or in an organic solvent, or in a mixtureof the two. Generally, non-aqueous media like ether, ethyl acetate,ethanol, isopropanol, or acetonitrile are typical, where practicable.Salts of the present compounds further include solvates of the compoundsand of the compound salts.

Examples of pharmaceutically acceptable salts include, but are notlimited to, mineral or organic acid salts of basic residues such asamines; alkali or organic salts of acidic residues such as carboxylicacids; and the like. The pharmaceutically acceptable salts include theconventional non-toxic salts and the quaternary ammonium salts of theparent compound formed, for example, from non-toxic inorganic or organicacids. For example, conventional non-toxic acid salts include thosederived from inorganic acids such as hydrochloric, hydrobromic,sulfuric, sulfamic, phosphoric, nitric and the like; and the saltsprepared from organic acids such as acetic, propionic, succinic,glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic,maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic,mesylic, esylic, besylic, sulfanilic, 2-acetoxybenzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic,HOOC—(CH₂)_(n)—COOH where n is 0-4, and the like. Lists of additionalsuitable salts may be found, e.g., in Remington's PharmaceuticalSciences, 17th ed., Mack Publishing Company, Easton, Pa., p. 1418(1985).

The term “carrier” applied to pharmaceutical compositions/combinationsof the invention refers to a diluent, excipient, or vehicle with whichan active compound is provided.

A “pharmaceutically acceptable excipient” means an excipient that isuseful in preparing a pharmaceutical composition/combination that isgenerally safe, non-toxic and neither biologically nor otherwiseinappropriate for administration to a host, and includes, in oneembodiment, an excipient that is acceptable for veterinary use as wellas human pharmaceutical use. A “pharmaceutically acceptable excipient”as used in the present application includes both one and more than onesuch excipient.

Compounds of the present invention may optionally be administered inconjunction with other compounds. The other compounds may optionally beadministered concurrently. As used herein, the word “concurrently” meanssufficiently close in time to produce a combined effect (that is,concurrently may be simultaneously, or it may be two or more eventsoccurring within a short time period before or after each other).

The present invention is primarily focused on the treatment of a humansubject or host, but the invention may be used to treat animals, such asmammalian subjects such as mice, rats, dogs, cats, livestock and horsesfor veterinary purposes, and for drug screening and drug developmentpurposes. Subjects may be of any age, including infant, juvenile,adolescent, adult, and geriatric subjects.

2. Detailed Description of Active Compounds

It has been discovered that the pyrazolopyrimidine compounds describedherein are potent inhibitors of MerTK activity and are superior asanti-thrombotic or anti-clotting agents, anti-infective agents,anti-cancer agents, and/or immunomodulatory agents.

The MerTK inhibitors useful in treating a disorder described herein havethe structure of Formula I:

wherein:

R¹ is aryl such as phenyl (in some embodiments substituted 1, 2 or 3times with heterocycloalkylalkyl, which heterocycloalkylalkyl issubstituted or unsubstituted, for example substituted from 1 to 3 timeswith halo, or alkyl). In some embodiments, heterocycloalkylalkyl is asubstituent of the formula —R′R″, where R′ is substituted orunsubstituted C1-C2 alkyl, and R″ is a heterocyclo group, such as anoptionally substituted piperazine or morpholine group.

R² is —R⁵R⁶, where R⁵ is a covalent bond or C₁ to C₃ alkyl and R⁶ iscycloalkyl, heterocycloalkyl, aryl, heteroaryl or alkyl, and wherein R⁶is optionally substituted from one to two times with independentlyselected polar groups;

R³ is —NR⁷R⁸, where R⁷ and R⁸ are each independently selected from H,alkyl, arylalkyl; and alkoxyalkyl (typically one of R⁷ or R⁸ is H); and

R⁴ is H, loweralkyl, halo, or loweralkoxy;

or a pharmaceutically acceptable composition, salt, isotopic analog, orprodrug thereof.

In another aspect, the present invention provides active compounds ofFormula II:

wherein:

R¹¹ is —R⁹(R¹⁰)_(n), where R⁹ is alkyl, alkenyl, -alkylaryl,heterocyclo, aryl, heteroaryl and R¹⁰ is hydrogen, alkyl, haloalkyl,alkoxyalkyl, —O-alkylaryl, hydroxyalkyl, alkenyl, alkenyloxy, alkynyl,alkynyloxy, cycloalkyl, cycloalkylalkyl, cycloalkoxy,cycloalkylalkyloxy, heterocyclo, heterocycloalkyl,alkylheterocycloalkyl, heterocyclooxy, heterocyclolalkyloxy, aryl,arylalkyl, aryloxy, arylalkyloxy, heteroaryl, alkylheteroaryl, halo,hydroxyl, alkoxy, haloalkoxy, mercapto, alkyl-S(O)_(m)—,haloalkyl-S(O)_(m)—, alkenyl-S(O)_(m)—, alkynyl-S(O)_(m)—,cycloalkyl-S(O)_(m)—, cycloalkylalkyl-S(O)_(m)—, aryl-S(O)_(m)—,arylalkyl-S(O)_(m)—, heterocyclo-S(O)_(m)—, heterocycloalkyl-S(O)_(m)—,amino, carboxy, alkylamino, —(CH₂)_(m)—NHalkyl, —(CH₂)_(m)—N(alkyl)₂,—(CH₂)_(m)—NH(CH₂)_(m)OH, —(CH₂)_(m)—NH(CH₂)_(m)cycloalkyl,—(CH₂)_(m)—NH(CH₂)₂₋₃heterocyclo, —(CH₂)_(m)—NH(CH₂)_(m)aryl,—(CH₂)_(m)—NH(CH₂)₂₋₃heteroaryl, —(CH₂)_(m)NH(CH₂)₂₋₃N(alkyl)₂,alkenylamino, alkynylamino, haloalkylamino, cycloalkylamino,cycloalkylalkylamino, arylamino, arylalkylamino, heterocycloamino,heterocycloalkylamino, disubstitutedamino, acylamino, acyloxy, ester,amide, S(O)₂OR²², CONHNH₂, cyano, nitro, aminosulfonyl, COOH,sulfonamide, urea, alkoxyacylamino, aminoacyloxy, —C(CH₂)₂R²², andwherein R¹⁰ is optionally substituted one, two or three times;

m=0, 1, 2 or 3;

n=0, 1 or 2;

R¹² is —R¹⁵R¹⁶, where R¹⁵ is a covalent bond or C₁ to C₃ alkyl and R¹⁶is cycloalkyl, cycloalkylalkyl, heterocyclo, heterocycloalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl hydroxyalkyl, alkoxyalkyl, oralkyl, and wherein R¹⁶ is optionally substituted one, two or threetimes;

R¹³ is NR¹⁷R¹⁸, where;

R¹⁷ is selected from the group consisting of H, alkyl, haloalkyl,hydroxyalkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclo,heterocycloalkyl, alkylheterocycloalkyl, heteroaryl, heteroaryalkyl, andalkoxyalkyl, each of which is optionally substituted one, two or threetimes (typically R¹⁷ is H);

R¹⁸ is selected from the group consisting of H, alkyl, haloalkyl,hydroxyalkyl, aryl, arylalkyl; cycloalkyl, cycloalkylalkyl, heterocyclo,heterocycloalkyl, alkylheterocycloalkyll, heteroaryl, heteroaryalkyl,and alkoxyalkyl, each of which is optionally substituted one, two orthree times; or

R¹⁷ and R¹⁸ together with the nitrogen to which they are bonded can forma heterocyclic group that can be optionally substituted;

R¹⁴ is H, loweralkyl, halo, or loweralkoxy;

R²² is selected from alkyl, alkenyl, alkynyl, aryl, arylalkyl,cycloalkyl, cycloalkylalkyl, heterocyclo, heterocycloalkyl, heteroaryl,or heteroarylalkyl;

or a pharmaceutically acceptable composition, salt, isotopic analog, orprodrug thereof.

In some embodiments of the foregoing, R¹ is phenyl or pyridyl, whichphenyl or pyridyl is unsubstituted or substituted from 1 to 3 times withhalo, amino, nitro, alkyl, alkoxyl, haloalkyl, cycloalkyl,heterocycloalkylalkyl, aryl, or heteroaryl.

In some embodiments of the foregoing R⁵ is —CH₂—.

In some embodiments of the foregoing, R⁸ is C₁-C₈ alkyl, C₃-C₈cycloalkyl, or C₁-C₈ alkyl aryl.

In some embodiments of the foregoing, R⁶ is cyclohexyl.

In some embodiments of the foregoing, R⁶ is substituted once with aminoor hydroxy.

In some embodiments of the foregoing, R⁷ is H.

In some embodiments of the foregoing, R⁸ is loweralkyl.

In some embodiments of the foregoing, R⁴ is H.

In some embodiments of the foregoing, R¹¹ is phenyl or pyridyl, whichphenyl or pyridyl is unsubstituted or substituted from 1 to 3 times withhalo, amino, nitro, alkyl, alkoxyl, haloalkyl, cycloalkyl,heterocycloalkylalkyl, aryl, or heteroaryl.

In some embodiments of the foregoing R¹⁵ is —CH₂—.

In some embodiments of the foregoing, R¹⁸ is C₁-C₈ alkyl, C₃-C₈cycloalkyl, or C₁-C₈ alkyl aryl.

In some embodiments of the foregoing, R¹⁶ is cyclohexyl.

In some embodiments of the foregoing, R¹⁶ is substituted once with aminoor hydroxy.

In some embodiments of the foregoing, R¹⁷ is H.

In some embodiments of the foregoing, R¹⁸ is loweralkyl.

In some embodiments of the foregoing, R¹⁴ is H.

In some embodiments, structures are provided including Formula II,wherein R¹⁴ and R¹⁷ are H, R¹³ is NR¹⁷R¹⁸, R¹¹ is aryl, R¹² iscycloalkyl, and R¹⁸ is loweralkyl, any of which can be optionallysubstituted.

In some embodiments, structures are provided including Formula II,wherein R¹⁴ and R¹⁷ are H, R¹³ is NR¹⁷R¹⁸, R¹¹ is aryl, R¹² iscyclohexyl, and R¹⁸ is loweralkyl, any of which can be optionallysubstituted.

In some embodiments, structures are provided including Formula II,wherein R¹⁴ and R¹⁷ are H, R¹³ is NR¹⁷R¹⁸, R¹¹ is aryl, R¹² ispara-hydroxy cyclohexyl, and R¹⁸ is loweralkyl, any of which can beoptionally substituted.

In some embodiments, structures are provided including Formula II,wherein R¹⁴ and R¹⁷ are H, R¹³ is NR¹⁷R¹⁸, R¹¹ is heteroaryl, R¹² iscycloalkyl, and R¹⁸ is loweralkyl, any of which can be optionallysubstituted.

In some embodiments, structures are provided including Formula II,wherein R¹⁴ and R¹⁷ are H, R¹³ is NR¹⁷R¹⁸, R¹¹ is heteroaryl, R¹² iscyclohexyl, and R¹⁸ is loweralkyl, any of which can be optionallysubstituted.

In some embodiments, structures are provided including Formula II,wherein R¹⁴ and R¹⁷ are H, R¹³ is NR¹⁷R¹⁸, R¹¹ is heteroaryl, R¹² ispara-hydroxy cyclohexyl, and R¹⁸ is loweralkyl, any of which can beoptionally substituted.

In some embodiments, structures are provided including Formula II,wherein R¹⁴ and R¹⁷ are H, R¹³ is NR¹⁷R¹⁸, R¹¹ is phenyl, R¹² iscycloalkyl, and R¹⁸ is loweralkyl, any of which can be optionallysubstituted.

In some embodiments, structures are provided including Formula II,wherein R¹⁴ and R¹⁷ are H, R¹³ is NR¹⁷R¹⁸, R¹¹ is phenyl, R¹² iscyclohexyl, and R¹⁸ is loweralkyl, any of which can be optionallysubstituted.

In some embodiments, structures are provided including Formula II,wherein R¹⁴ and R¹⁷ are H, R¹³ is NR¹⁷R¹⁸, R¹¹ is phenyl, R¹² ispara-hydroxy cyclohexyl, and R¹⁸ is loweralkyl, any of which can beoptionally substituted.

In some embodiments, structures are provided including Formula II,wherein R¹⁴ and R¹⁷ are H, R¹³ is NR¹⁷R¹⁸, R¹¹ is aryl, R¹² iscycloalkyl, and R¹⁸ is butyl, any of which can be optionallysubstituted.

In some embodiments, structures are provided including Formula II,wherein R¹⁴ and R¹⁷ are H, R¹³ is NR¹⁷R¹⁸, R¹¹ is aryl, R¹² iscyclohexyl, and R¹⁸ is butyl, any of which can be optionallysubstituted.

In some embodiments, structures are provided including Formula II,wherein R¹⁴ and R¹⁷ are H, R¹³ is NR¹⁷R¹⁸, R¹¹ is aryl, R¹² ispara-hydroxy cyclohexyl, and R¹⁸ is butyl, any of which can beoptionally substituted.

In some embodiments, structures are provided including Formula II,wherein R¹⁴ and R¹⁷ are H, R¹³ is NR¹⁷R¹⁸, R¹¹ is heteroaryl, R¹² iscycloalkyl, and R¹⁸ is butyl, any of which can be optionallysubstituted.

In some embodiments, structures are provided including Formula II,wherein R¹⁴ and R¹⁷ are H, R¹³ is NR¹⁷R¹⁸, R¹¹ is heteroaryl, R¹² iscyclohexyl, and R¹⁸ is butyl, any of which can be optionallysubstituted.

In some embodiments, structures are provided including Formula II,wherein R¹⁴ and R¹⁷ are H, R¹³ is NR¹⁷R¹⁸, R¹¹ is heteroaryl, R¹² ispara-hydroxy cyclohexyl, and R¹⁸ is butyl, any of which can beoptionally substituted.

In some embodiments, structures are provided including Formula II,wherein R¹⁴ and R¹⁷ are H, R¹³ is NR¹⁷R¹⁸, R¹¹ is phenyl, R¹² iscycloalkyl, and R¹⁸ is butyl, any of which can be optionallysubstituted.

In some embodiments, structures are provided including Formula II,wherein R¹⁴ and R¹⁷ are H, R¹³ is NR¹⁷R¹⁸, R¹¹ is phenyl, R¹² iscyclohexyl, and R¹⁸ is butyl, any of which can be optionallysubstituted.

In some embodiments, structures are provided including Formula II,wherein R¹⁴ and R¹⁷ are H, R¹³ is NR¹⁷R¹⁸, R¹¹ is phenyl, R¹² ispara-hydroxy cyclohexyl, and R¹⁸ is butyl, any of which can beoptionally substituted.

In some embodiments, structures are provided including Formula II,wherein R¹⁴ and R¹⁷ are H, R¹³ is NR¹⁷R¹⁸, R¹¹ is aryl, R¹² iscycloalkyl, and R¹⁸ is cycloalkylalkyl, any of which can be optionallysubstituted.

In some embodiments, structures are provided including Formula II,wherein R¹⁴ and R¹⁷ are H, R¹³ is NR¹⁷R¹⁸, R¹¹ is aryl, R¹² iscyclohexyl, and R¹⁸ is cycloalkylalkyl, any of which can be optionallysubstituted.

In some embodiments, structures are provided including Formula II,wherein R¹⁴ and R¹⁷ are H, R¹³ is NR¹⁷R¹⁸, R¹¹ is aryl, R¹² ispara-hydroxy cyclohexyl, and R¹⁸ is cycloalkylalkyl, any of which can beoptionally substituted.

In some embodiments, structures are provided including Formula II,wherein R¹⁴ and R¹⁷ are H, R¹³ is NR¹⁷R¹⁸, R¹¹ is heteroaryl, R¹² iscycloalkyl, and R¹⁸ is cycloalkylalkyl, any of which can be optionallysubstituted.

In some embodiments, structures are provided including Formula II,wherein R¹⁴ and R¹⁷ are H, R¹³ is NR¹⁷R¹⁸, R¹¹ is heteroaryl, R¹² iscyclohexyl, and R¹⁸ is cycloalkylalkyl, any of which can be optionallysubstituted.

In some embodiments, structures are provided including Formula II,wherein R¹⁴ and R¹⁷ are H, R¹³ is NR¹⁷R¹⁸, R¹¹ is heteroaryl, R¹² ispara-hydroxy cyclohexyl, and R¹⁸ is cycloalkylalkyl, any of which can beoptionally substituted.

In some embodiments, structures are provided including Formula II,wherein R¹⁴ and R¹⁷ are H, R¹³ is NR¹⁷R¹⁸, R¹¹ is phenyl, R¹² iscycloalkyl, and R¹⁸ is cycloalkylalkyl, any of which can be optionallysubstituted.

In some embodiments, structures are provided including Formula II,wherein R¹⁴ and R¹⁷ are H, R¹³ is NR¹⁷R¹⁸, R¹¹ is phenyl, R¹² iscyclohexyl, and R¹⁸ is cycloalkylalkyl, any of which can be optionallysubstituted.

In some embodiments, structures are provided including Formula II,wherein R¹⁴ and R¹⁷ are H, R¹³ is NR¹⁷R¹⁸, R¹¹ is phenyl, R¹² ispara-hydroxy cyclohexyl, and R¹⁸ is cycloalkylalkyl, any of which can beoptionally substituted.

In some embodiments, structures are provided including Formula II,wherein R¹⁴ and R¹⁷ are H, R¹³ is NR¹⁷R¹⁸, R¹¹ is aryl, R¹² iscycloalkyl, and R¹⁸ is aryl, any of which can be optionally substituted.

In some embodiments, structures are provided including Formula II,wherein R¹⁴ and R¹⁷ are H, R¹³ is NR¹⁷R¹⁸, R¹¹ is aryl, R¹² iscyclohexyl, and R¹⁸ is aryl, any of which can be optionally substituted.

In some embodiments, structures are provided including Formula II,wherein R¹⁴ and R¹⁷ are H, R¹³ is NR¹⁷R¹⁸, R¹¹ is aryl, R¹² ispara-hydroxy cyclohexyl, and R¹⁸ is aryl, any of which can be optionallysubstituted.

In some embodiments, structures are provided including Formula II,wherein R¹⁴ and R¹⁷ are H, R¹³ is NR¹⁷R¹⁸, R¹¹ is heteroaryl, R¹² iscycloalkyl, and R¹⁸ is aryl, any of which can be optionally substituted.

In some embodiments, structures are provided including Formula II,wherein R¹⁴ and R¹⁷ are H, R¹³ is NR¹⁷R¹⁸, R¹¹ is heteroaryl, R¹² iscyclohexyl, and R¹⁸ is aryl, any of which can be optionally substituted.

In some embodiments, structures are provided including Formula II,wherein R¹⁴ and R¹⁷ are H, R¹³ is NR¹⁷R¹⁸, R¹¹ is heteroaryl, R¹² ispara-hydroxy cyclohexyl, and R¹⁸ is aryl, any of which can be optionallysubstituted.

In some embodiments, structures are provided including Formula II,wherein R¹⁴ and R¹⁷ are H, R¹³ is NR¹⁷R¹⁸, R¹¹ is phenyl, R¹² iscycloalkyl, and R¹⁸ is aryl, any of which can be optionally substituted.

In some embodiments, structures are provided including Formula II,wherein R¹⁴ and R¹⁷ are H, R¹³ is NR¹⁷R¹⁸, R¹¹ is phenyl, R¹² iscyclohexyl, and R¹⁸ is aryl, any of which can be optionally substituted.

In some embodiments, structures are provided including Formula II,wherein R¹⁴ and R¹⁷ are H, R¹³ is NR¹⁷R¹⁸, R¹¹ is phenyl, R¹² ispara-hydroxy cyclohexyl, and R¹⁸ is aryl, any of which can be optionallysubstituted.

In some embodiments, structures are provided including Formula II,wherein R¹⁴ and R¹⁷ are H, R¹³ is NR¹⁷R¹⁸, R¹¹ is aryl, R¹² iscycloalkyl, and R¹⁸ is phenyl, any of which can be optionallysubstituted.

In some embodiments, structures are provided including Formula II,wherein R¹⁴ and R¹⁷ are H, R¹³ is NR¹⁷R¹⁸, R¹¹ is aryl, R¹² iscyclohexyl, and R¹⁸ is phenyl, any of which can be optionallysubstituted.

In some embodiments, structures are provided including Formula II,wherein R¹⁴ and R¹⁷ are H, R¹³ is NR¹⁷R¹⁸, R¹¹ is aryl, R¹² ispara-hydroxy cyclohexyl, and R¹⁸ is phenyl, any of which can beoptionally substituted.

In some embodiments, structures are provided including Formula II,wherein R¹⁴ and R¹⁷ are H, R¹³ is NR¹⁷R¹⁸, R¹¹ heteroaryl, R¹² iscycloalkyl, and R¹⁸ is phenyl, any of which can be optionallysubstituted.

In some embodiments, structures are provided including Formula II,wherein R¹⁴ and R¹⁷ are H, R¹³ is NR¹⁷R¹⁸, R¹¹ is heteroaryl, R¹² iscyclohexyl, and R¹⁸ is phenyl, any of which can be optionallysubstituted.

In some embodiments, structures are provided including Formula II,wherein R¹⁴ and R¹⁷ are H, R¹³ is NR¹⁷R¹⁸, R¹¹ is heteroaryl, R¹² ispara-hydroxy cyclohexyl, and R¹⁸ is phenyl, any of which can beoptionally substituted.

In one embodiment, the compounds useful in the present invention aredual MER/FLT-3 TKIs. In one embodiment, the compounds are dual FLT3/AxlTKIs.

In one embodiment, the compound has the structure of Formula III:

wherein:R¹⁹ is heterocycle;R²⁰ and R²¹ are each independently hydrogen, alkyl, cycloalkyl, orcycloalkylalkyl.

In one embodiment, the compound is Formula IV having the structuredepicted below:

Active compounds may be provided as pharmaceutically acceptableprodrugs, which are those prodrugs of the active compounds of thepresent invention which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like,commensurate with a reasonable risk/benefit ratio, and effective fortheir intended use, as well as the zwitterionic forms, where possible,of the compounds of the invention. The term “prodrug” refers tocompounds that are transformed, sometimes rapidly in vivo to yield theparent compound of the above formulae, for example, by hydrolysis inblood. A thorough discussion is provided in T. Higuchi and V. Stella,Prodrugs as Novel delivery Systems, Vol. 14 of the A.C.S. SymposiumSeries and in Edward B. Roche, ed., Bioreversible Carriers in DrugDesign, American Pharmaceutical Association and Pergamon Press, 1987,both of which are incorporated by reference herein. See also U.S. Pat.No. 6,680,299 Examples include a prodrug that is metabolized in vivo bya subject to an active drug having an activity of active compounds asdescribed herein, wherein the prodrug is an ester of an alcohol orcarboxylic acid group, if such a group is present in the compound; anacetal or ketal of an alcohol group, if such a group is present in thecompound; an N-Mannich base or an imine of an amine group, if such agroup is present in the compound; or a Schiff base, oxime, acetal, enolester, oxazolidine, or thiazolidine of a carbonyl group, if such a groupis present in the compound, such as described in U.S. Pat. No. 6,680,324and U.S. Pat. No. 6,680,322.

The active compounds disclosed herein can, as noted above, be providedin the form of their pharmaceutically acceptable salts. Pharmaceuticallyacceptable salts are salts that retain the desired biological activityof the parent compound and do not impart undesired toxicologicaleffects. Nonlimiting examples of such salts are (a) acid addition saltsformed with inorganic acids, for example hydrochloric acid, hydrobromicacid, sulfuric acid, phosphoric acid, nitric acid and the like; andsalts formed with organic acids such as, for example, acetic acid,oxalic acid, tartaric acid, succinic acid, maleic acid, fumaric acid,gluconic acid, citric acid, malic acid, ascorbic acid, benzoic acid,tannic acid, palmitic acid, alginic acid, polyglutamic acid,naphthalenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid,naphthalenedisulfonic acid, polygalacturonic acid, and the like; (b)salts formed from elemental anions such as chlorine, bromine, andiodine, and (c) salts derived from bases, such as ammonium salts, alkalimetal salts such as those of sodium and potassium, alkaline earth metalsalts such as those of calcium and magnesium, and salts with organicbases such as dicyclohexylamine and N-methyl-D-glucamine.

Active compounds as described herein can be prepared in accordance withknown procedures, or variations thereof that will be apparent to thoseskilled in the art.

3. Pharmaceutical Compositions and Dosages for all Indications

The active compounds described above may be formulated foradministration in a pharmaceutical carrier in accordance with knowntechniques. See, e.g., Remington, The Science And Practice of Pharmacy(9^(th) Ed. 1995). In the manufacture of a pharmaceutical formulationaccording to the invention, the active compound (including thephysiologically acceptable salts thereof) is typically admixed with,inter alia, an acceptable carrier. The carrier must, of course, beacceptable in the sense of being compatible with any other ingredientsin the formulation and must not be deleterious to the patient. Thecarrier may be a solid or a liquid, or both, and is preferablyformulated with the compound as a unit-dose formulation, for example, atablet, which may contain from 0.01 or 0.5% to 95% or 99% by weight ofthe active compound. One or more active compounds may be incorporated inthe formulations of the invention, which may be prepared by any of thewell-known techniques of pharmacy comprising admixing the components,optionally including one or more accessory ingredients.

In one aspect, the invention provides a pharmaceutical compositioncomprising a pharmaceutically effective amount of an active compound asdescribed herein and a pharmaceutically acceptable carrier.

The compounds provided herein are administered for medical therapy in atherapeutically effective amount. The amount of the compoundsadministered will typically be determined by a physician, in the lightof the relevant circumstances, including the condition to be treated,the chosen route of administration, the compound administered, the age,weight, and response of the individual patient, the severity of thepatient's symptoms, and the like.

The formulations of the invention include those suitable for oral,rectal, topical, buccal (e.g., sub-lingual), vaginal, parenteral (e.g.,subcutaneous, intramuscular, intradermal, or intravenous), topical(i.e., both skin and mucosal surfaces, including airway surfaces),transdermal administration, and intraventricular injection (injectioninto a ventricle of the brain, e.g., by an implanted catheter or ommanreservoir, such as in the case of morbid obesity), ocular (viainjection, implantation or by reservoir), and intranasal, although themost suitable route in any given case will depend on the nature andseverity of the condition being treated and on the nature of theparticular active compound which is being used.

The compositions for oral administration can take the form of bulkliquid solutions or suspensions, or bulk powders. Typically, thecompositions are presented in unit dosage forms to facilitate accuratedosing. The term “unit dosage forms” refers to physically discrete unitssuitable as unitary dosages for human subjects and other mammals, eachunit containing a predetermined quantity of active material calculatedto produce the desired therapeutic effect, in association with asuitable pharmaceutical excipient. Typical unit dosage forms includeprefilled, premeasured ampules or syringes of the liquid compositions orpills, tablets, capsules or the like in the case of solid compositions.In such compositions, the compound is usually a minor component (as anonlimiting example, from about 0.1 to about 50% by weight or preferablyfrom about 1 to about 40% by weight) with the remainder being variousvehicles or carriers and processing aids helpful for forming the desireddosing form. In one embodiment, the compound is present from about 1% toabout 10% by weight.

Liquid forms suitable for oral administration may include a suitableaqueous or nonaqueous vehicle with buffers, suspending and dispensingagents, colorants, flavors and the like. Solid forms may include, forexample, any of the following ingredients, or compounds of a similarnature: a binder such as microcrystalline cellulose, gum tragacanth orgelatin; an excipient such as starch or lactose, a disintegrating agentsuch as alginic acid, Primogel, or corn starch; a lubricant such asmagnesium stearate; a glidant such as colloidal silicon dioxide; asweetening agent such as sucrose or saccharin; or a flavoring agent suchas peppermint, methyl salicylate, or orange flavoring.

Formulations suitable for oral administration may be presented indiscrete units, such as capsules, cachets, lozenges, or tablets, eachcontaining a predetermined amount of the active compound; as a powder orgranules; as a solution or a suspension in an aqueous or non-aqueousliquid; or as an oil-in-water or water-in-oil emulsion. Suchformulations may be prepared by any suitable method of pharmacy whichincludes the step of bringing into association the active compound and asuitable carrier (which may contain one or more accessory ingredients asnoted above). In general, the formulations of the invention are preparedby uniformly and intimately admixing the active compound with a liquidor finely divided solid carrier, or both, and then, if necessary,shaping the resulting mixture. For example, a tablet may be prepared bycompressing or molding a powder or granules containing the activecompound, optionally with one or more accessory ingredients. Compressedtablets may be prepared by compressing, in a suitable machine, thecompound in a free-flowing form, such as a powder or granules optionallymixed with a binder, lubricant, inert diluent, and/or surfaceactive/dispersing agent(s). Molded tablets may be made by molding, in asuitable machine, the powdered compound moistened with an inert liquidbinder. In one embodiment, the compounds are administered in acontrolled release formulation.

Formulations suitable for buccal (sub-lingual) administration includelozenges comprising the active compound in a flavored base, usuallysucrose and acacia or tragacanth; and pastilles comprising the compoundin an inert base such as gelatin and glycerin or sucrose and acacia.

Formulations of the present invention suitable for parenteraladministration comprise sterile aqueous and non-aqueous injectionsolutions of the active compound, which preparations are preferablyisotonic with the blood of the intended recipient. These preparationsmay contain anti-oxidants, buffers, bacteriostats and solutes whichrender the formulation isotonic with the blood of the intendedrecipient. Aqueous and non-aqueous sterile suspensions may includesuspending agents and thickening agents. The formulations may bepresented in unit\dose or multi-dose containers, for example sealedampoules and vials, and may be stored in a freeze-dried (lyophilized)condition requiring only the addition of the sterile liquid carrier, forexample, saline or water-for-injection immediately prior to use.Extemporaneous injection solutions and suspensions may be prepared fromsterile powders, granules and tablets of the kind previously described.For example, in one aspect of the present invention, there is providedan injectable, stable, sterile composition comprising a compound ofFormula (I), or a salt thereof, in a unit dosage form in a sealedcontainer. The compound or salt is provided in the form of alyophilizate which is capable of being reconstituted with a suitablepharmaceutically acceptable carrier to form a liquid compositionsuitable for injection thereof into a subject. The unit dosage formtypically comprises from about 10 mg to about 10 grams of the compoundor salt. When the compound or salt is substantially water-insoluble, asufficient amount of emulsifying agent which is physiologicallyacceptable may be employed in sufficient quantity to emulsify thecompound or salt in an aqueous carrier. One such useful emulsifyingagent is phosphatidyl choline.

Injectable compositions are typically based upon injectable sterilesaline or phosphate-buffered saline or other injectable carriers knownin the art.

Formulations suitable for rectal administration are preferably presentedas unit dose suppositories. These may be prepared by admixing the activecompound with one or more conventional solid carriers, for example,cocoa butter, and then shaping the resulting mixture.

Formulations suitable for topical application to the skin preferablytake the form of an ointment, cream, lotion, paste, gel, spray, aerosol,or oil. Carriers which may be used include petroleum jelly, lanoline,polyethylene glycols, alcohols, transdermal enhancers, and combinationsof two or more thereof.

Formulations suitable for transdermal administration may be presented asdiscrete patches adapted to remain in intimate contact with theepidermis of the recipient for a prolonged period of time. Formulationssuitable for transdermal administration may also be delivered byiontophoresis (see, for example, Pharmaceutical Research 3 (6):318(1986)) and typically take the form of an optionally buffered aqueoussolution of the active compound. Suitable formulations comprise citrateor bis\tris buffer (pH 6) or ethanol/water and contain from 0.1 to 0.2Mactive ingredient.

Further, the present invention provides liposomal formulations of thecompounds disclosed herein and salts thereof. The technology for formingliposomal suspensions is well known in the art. When the compound orsalt thereof is an aqueous-soluble salt, using conventional liposometechnology, the same may be incorporated into lipid vesicles. In such aninstance, due to the water solubility of the compound or salt, thecompound or salt will be substantially entrained within the hydrophiliccenter or core of the liposomes. The lipid layer employed may be of anyconventional composition and may either contain cholesterol or may becholesterol-free. When the compound or salt of interest iswater-insoluble, again employing conventional liposome formationtechnology, the salt may be substantially entrained within thehydrophobic lipid bilayer which forms the structure of the liposome. Ineither instance, the liposomes which are produced may be reduced insize, as through the use of standard sonication and homogenizationtechniques.

Of course, the liposomal formulations containing the compounds disclosedherein or salts thereof, may be lyophilized to produce a lyophilizatewhich may be reconstituted with a pharmaceutically acceptable carrier,such as water, to regenerate a liposomal suspension.

Other pharmaceutical compositions may be prepared from thewater-insoluble compounds disclosed herein, or salts thereof, such asaqueous base emulsions. In such an instance, the composition willcontain a sufficient amount of pharmaceutically acceptable emulsifyingagent to emulsify the desired amount of the compound or salt thereof.Particularly useful emulsifying agents include phosphatidyl cholines,and lecithin.

In addition to compounds of Formula I, II, III, or IV, or other activecompounds described herein, or their salts, the pharmaceuticalcompositions may contain other additives, such as pH-adjustingadditives. In particular, useful pH-adjusting agents include acids, suchas hydrochloric acid, bases or buffers, such as sodium lactate, sodiumacetate, sodium phosphate, sodium citrate, sodium borate, or sodiumgluconate. Further, the compositions may contain microbialpreservatives. Useful microbial preservatives include methylparaben,propylparaben, and benzyl alcohol. The microbial preservative istypically employed when the formulation is placed in a vial designed formultidose use. Of course, as indicated, the pharmaceutical compositionsof the present invention may be lyophilized using techniques well knownin the art.

The Mer TKI compound of this invention can also be administered insustained release forms or from sustained release drug delivery systems.A description of representative sustained release materials can be foundin Remington's Pharmaceutical Sciences.

In certain embodiments, the formulation comprises water. In anotherembodiment, the formulation comprises a cyclodextrin derivative. Incertain embodiments, the formulation compriseshexapropyl-β-cyclodextrin. In a more particular embodiment, theformulation comprises hexapropyl-β-cyclodextrin (10-50% in water).

The present invention also includes pharmaceutically acceptable acidaddition salts of compounds of the compounds of the invention. The acidswhich are used to prepare the pharmaceutically acceptable salts arethose which form non-toxic acid addition salts, i.e. salts containingpharmacologically acceptable anions such as the hydrochloride,hydroiodide, hydrobromide, nitrate, sulfate, bisulfate, phosphate,acetate, lactate, citrate, tartrate, succinate, maleate, fumarate,benzoate, para-toluenesulfonate, and the like.

The above-described components for pharmaceutical compositions aremerely representative. Other materials as well as processing techniquesand the like are set forth in Part 8 of Remington's PharmaceuticalSciences, 17th edition, 1985, Mack Publishing Company, Easton, Pa.,which is incorporated herein by reference.

As noted above, the present invention provides pharmaceuticalformulations comprising the active compounds (including thepharmaceutically acceptable salts thereof), in pharmaceuticallyacceptable carriers for oral, rectal, topical, buccal, parenteral,intramuscular, intradermal, or intravenous, and transdermaladministration.

The therapeutically effective dosage of any specific compound, the useof which is in the scope of present invention, will vary somewhat fromcompound to compound, and patient to patient, and will depend upon thecondition of the patient and the route of delivery. As a generalproposition, a dosage from about 0.1 to about 50 mg/kg will havetherapeutic efficacy, with all weights being calculated based upon theweight of the active compound, including the cases where a salt isemployed. Toxicity concerns at the higher level may restrict intravenousdosages to a lower level such as up to about 10 mg/kg, with all weightsbeing calculated based upon the weight of the active base, including thecases where a salt is employed. The duration of the treatment can beonce per day for a period of two to three weeks or until the conditionis essentially controlled.

The therapeutically effective dosage of any active compound describedherein will be determined by the health care practitioner depending onthe condition, size and age of the patient as well as the route ofdelivery. In one non-limited embodiment, a dosage from about 0.1 toabout 200 mg/kg has therapeutic efficacy, with all weights beingcalculated based upon the weight of the active compound, including thecases where a salt is employed. In some embodiments, the dosage can bethe amount of compound needed to provide a serum concentration of theactive compound of up to between about 1 and 5, 10, 20, 30, or 40 μM. Insome embodiments, a dosage from about 10 mg/kg to about 50 mg/kg can beemployed for oral administration. Typically, a dosage from about 0.5mg/kg to 5 mg/kg can be employed for intramuscular injection. In someembodiments, dosages can be from about 1 μmol/kg to about 50 μmol/kg,or, optionally, between about 22 μmol/kg and about 33 μmol/kg of thecompound for intravenous or oral administration. An oral dosage form caninclude any appropriate amount of active material, including for examplefrom 5 mg to, 50, 100, 200, or 500 mg per tablet or other solid dosageform.

Active compounds may be administered as pharmaceutically acceptableprodrugs, which are those prodrugs of the active compounds of thepresent invention which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like,commensurate with a reasonable risk/benefit ratio, and effective fortheir intended use, as well as the zwitterionic forms, where possible,of the compounds of the invention. The term “prodrug” refers tocompounds that are rapidly transformed in vivo to yield the parentcompound of the above formulae, for example, by hydrolysis in blood. Athorough discussion is provided in T. Higuchi and V. Stella, Prodrugs asNovel delivery Systems, Vol. 14 of the A.C.S. Symposium Series and inEdward B. Roche, ed., Bioreversible Carriers in Drug Design, AmericanPharmaceutical Association and Pergamon Press, 1987, both of which areincorporated by reference herein. See also U.S. Pat. No. 6,680,299Examples include a prodrug that is metabolized in vivo by a subject toan active drug having an activity of active compounds as describedherein, wherein the prodrug is an ester of an alcohol or carboxylic acidgroup, if such a group is present in the compound; an acetal or ketal ofan alcohol group, if such a group is present in the compound; anN-Mannich base or an imine of an amine group, if such a group is presentin the compound; or a Schiff base, oxime, acetal, enol ester,oxazolidine, or thiazolidine of a carbonyl group, if such a group ispresent in the compound, such as described in U.S. Pat. No. 6,680,324and U.S. Pat. No. 6,680,322.

In one aspect of the invention, a method is provided to treat a host byadministering a daily amount of a Mer TKI including active compounds ofthe present invention, which may be provided in dosages once or more aday. In one embodiment, the Mer TKI dose is between about 0.5 mg andabout 200 mg. In one embodiment, the dose is at least about 1 mg, about2 mg, about 3 mg, about 4 mg, about 5 mg, about 10 mg, about 12 mg,about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg,about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about95 mg, about 100 mg, about 110 mg, about 125 mg, about 140 mg, about150, about 175, or about 200 mg. In another embodiment, the dose isbetween about 200 mg and 1250 mg. In one embodiment, the dose is about200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg, about825 mg, about 850 mg, about 875 mg, about 900 mg, about 925 mg, about950 mg, about 975 mg, about 1000 mg or more.

In one embodiment, the compounds described herein are combined with anadditional anti-tumor agent, anti-neoplastic agent, anti-cancer agent,immunomodulatory agent, immunostimulatory agent, anti-infective agents,anti-thrombotic, and/or anti-clotting agent. The dosage administered tothe host can be similar to that as administered during monotherapytreatment, or may be lower, for example, between about 0.5 mg and about150 mg. In one embodiment, the dose is at least about 1 mg, about 2 mg,about 3 mg, about 4 mg, about 5 mg, about 10 mg, about 12 mg, about 15mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg,about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg,about 100 mg, about 110 mg, about 125 mg, about 140 mg, or about 150 mg.

In one embodiment, for the case of the co-administration of an activecompound in combination with an additional anti-tumor agent,anti-neoplastic agent, anti-cancer agent, immunomodulatory agent,immunostimulatory agent, anti-infective agents, anti-thrombotic, and/oranti-clotting agent, as otherwise described herein, the amount of thecompound according to the present invention to be administered rangesfrom about 0.01 mg/kg of the patient to about 50 mg/kg or more of thepatient or considerably more, depending upon the second compound to beco-administered, the condition of the patient, severity of the diseaseto be treated, and the route of administration. In one embodiment, theadditional anti-tumor agent, anti-neoplastic agent, anti-cancer agent,immunomodulatory agent, immunostimulatory agent, anti-infective agents,anti-thrombotic, and/or anti-clotting agent may, for example, beadministered in amounts ranging from about 0.01 mg/kg to about 500mg/kg. In one embodiment, for oral dosing, suitable daily dosages are,for example, between about 0.1-4000 mg administered orally once-daily,twice-daily, or three times-daily, continuous (every day) orintermittently (e.g., 3-5 days a week).

Methods of Use of the Active Compounds 4. Anti-Infective Agents

It has been discovered that an effective amount of the pyrimidinylcompounds described in Formulas I, II, III and IV below or as otherwiseprovided herein, can be administered as an immunomodulatory agent tostimulate the innate immune system. This immunostimulatory activity canbe used therapeutically to treat a host with an infection. In oneembodiment, the infection is a viral infection. In one embodiment, theinfection is a bacterial infection. In an alternative embodiment, aneffective amount of the pyrimidinyl compounds described in Formulas I,II, III and IV below or as otherwise provided herein can be used totreat a host bearing any virus-related infection where the virus has avirion envelope phosphatidyl serine that complexes with MerTK to achieveviral entry or is otherwise facilitated by MerTK in the infectiousprocess or maintenance.

Viral Infections.

The virus may be an enveloped virus or a non-enveloped virus. In oneembodiment, the host is infected or threatened to become infected with avirus selected from, for example, Flaviviridae viruses, includingFlavivirus (such as Yellow Fever, West Nile and Dengue), Hepacivirus(Hepatitis C virus, “HCV”), Pegivirus and Pestivirus (Bovine viraldiarrhea virus); Filoviridae viruses, including Ebola viruses;Togaviridae viruses, including Chikungunya virus; Coronaviruses, such asSARS (Severe acute respiratory syndrome) and MERS (Middle Eastrespiratory syndrome); Orthomyxoviridae viruses, for example influenza;Paramyxoviridae viruses, for example Respiratory syncytial virus (RSV),measles and mumps; and Caliciviridae viruses, including Lagovirus,Vesivirus, and Sapovirus and Norovirus (Norwalk-like virus), andLentiviruses, for example, HIV. In one embodiment, an active compounddisclosed herein is administered in combination or alternation withanother anti-viral agent for combination therapy. In one embodiment, thecompound administered is UNC2207A.

More broadly, the host to be treated may be infected with an envelopedvirus including, but not limited to, viruses of the following families:Bornaviridae, Bunyaviridae, Coronaviridae, Filoviridae, Flaviridae,Hepadnaviridae, Herpesviridae, Nyamiviridae, Orthomyxoviridae,Paramyxoviridae, Poxyiridae, Retroviridae, Rhabdoviridae, andTogaviridae. Examples of viruses form the Bunyaviridae family include,but are not limited to, bunya viruses such as La Crosse virus andHantaan. Examples of viruses from the Coronaviridae family include, butare not limited to, coronaviruses such as SARS virus or Toroviruses.Examples of viruses from the Filoviradae family include, but are notlimited to, Ebola and Marburg. Examples of viruses from the Flaviridaefamily include, but are not limited to, dengue, encephalitis virusesincluding West Nile virus, Japanese encephalitis virus and yellow fevervirus and Hepatitis C virus. Examples of viruses from the Hepadnaviridaefamily include, but are not limited to, Hepatitis B. Examples of virusesfrom the Herpesviridae family include, but are not limited to,cytomegalovirus, herpes simplex viruses 1 and 2, HHV-6, HHV-7, HHV-8,pseudorabies virus, and varicella zoster virus. Examples of viruses fromthe Orthomyxoviridae family include, but are not limited to, influenzavirus. Examples of viruses from the Paramyxoviridae family include, butare not limited to, measles, metapneumovirus, mumps, parainfluenza,respiratory syncytial virus, and sendai. Examples of viruses from thePoxviridae family include, but are not limited to, pox viruses such assmallpox, monkey pox, and Molluscum contagiosum virus, variola viruses,vaccinia virus, and yatapox viruses such as Tanapox and Yabapox.Examples of viruses from the Retroviridae family include, but are notlimited to, Coltiviruses such as CTFV and Banna virus, humanimmunodeficiency viruses such as HIV-1 and HIV-2, murine leukemia virus,simian immunodeficiency virus, feline immunodeficiency virus, humanT-cell leukemia viruses 1 and 2, and XMRV. Examples of viruses from theRhabdoviridae family include, but are not limited to, vesicularstomatitis and rabies. Examples of viruses from the Togaviridae familyinclude, but are not limited to, rubella viruses or alpha viruses suchas Chikungunya virus, Eastern equine encephalitis virus, O'nyong'nyongvirus, Ross River virus, Semliki Forest virus, Sindbis, Venezuelanequine encephalitis or Western equine encephalitis virus.

In one embodiment, the host is infected with Chikungunya virus. In oneembodiment, the host is infected with Ebola virus. In one embodiment, anactive compound or Mer TKI as described herein is used in combinationwith brincidofovir (CMX001).

In another particular embodiment, the host is infected with anon-enveloped virus, sch as, but not limited to, viruses of thefollowing families. Adenoviridae, Arenaviridae, Birnaviridae,Calciviridae, Iridoviridae, Ophioviridae Parvoviradae, Papillomaviridae,Papovaviridae, Picornaviridae, and Reoviridae. Examples of viruses fromthe Adenoviridae family include, but are not limited to adenoviruses.Examples of viruses from the Arenaviradae family include, but are notlimited to, hemorrhagic fever viruses such as Guanarito, LCMV, Lassa,Junin, and Machupo. Examples of viruses from the Iridoviridae familyinclude, but are not limited to, African swine fever virus. Examples ofviruses from the Papillomavirus family include, but are not limited to,papillomaviruses. Examples of viruses from the Papovaviridae familyinclude, but are not limited to, polyoma viruses such as BK virus and JCvirus. Examples of viruses from the Parvoviridae family include, but arenot limited to, parvoviruses such as human bocavirus andadeno-associated virus. Examples of viruses from the Picornaviridaefamily include, but are not limited to, aptoviruses, cardioviruses,coxsackieviruses, echoviruses, enteric viruses, enteroviruses, foot andmouth disease virus, hepatitis A virus, hepatoviruses, Poliovirus, andrhinovirus. Examples of viruses from the Reoviradae family include, butare not limited to, orbiviruses, reoviruses and rotaviruses.

In another embodiment, a host is infected with a virus such as anastroviruses, caliciviruses including but not limited to, Norovirus andNorwalk, and Hepeviruses including, but not limited to, Hepatitis E.

As described above, a compound described herein can be administered to ahost suffering from a viral infection in combination with anotheranti-viral or anti-infective compound. Antiviral compounds that can beused in combination with the compounds described herein include, but arenot limited to, abacavir, acyclovir, adefovir, amantadine, amprenavir,ampligen, arbitol, atazanavir, balavir, boceprevir, boceprevirertet,cidofovir, dolutegravir, darunavir, delavirdine, didanosine, docosanol,edoxudine, efavirenz, emtricitabine, epivir, enfuvirtide, entecavir,famciclovir, fomivirsen, fosamprenavir, foscarnet, fosfonet,ganciclovir, ibacitabine, imunovir, idoxuridine, imiquimod, indinavir,lamivudine, lopinavir, loviride, maraviroc, moroxydine, nelfinavir,nevirapine, nexavir, oseltamivir, penciclovir, peramivir, pleconaril,podophyllotoxin, raltegravir, ribavirin, rilpivirine, rimantadine,pyramidine, saquinavir, simeprevir, sofosbuvir, stavudine, telaprevir,tenofovir, tipranavir, trifluridine, trizivir, tromantadine, traporved,truvada, valaciclovir, valganciclovir, vicriviroc, vidarabine,viramidine, zalcitabine, zanamivir, and zidovudine.

In one embodiment, a host is infected with a human immunodeficiencyvirus and is administered a compound described herein in combinationwith the anti-HIV combination drug, such as Atripla® or other drug thatincludes emtricitabine. In another embodiment, the patient with thehuman immunodeficiency virus can be treated with atazanavir, ritonavir,or Truvada® in combination with a compound described herein. In anotherembodiment, the patient infected with human immunodeficiency virus canbe treated with the combination of dolutegravir, Truvada® and a compounddescribed herein. In another embodiment, human immunodeficiency viruscan be treated with the combination dolutegravir, Epzicom® and acompound described herein. In another embodiment, a host infected withhuman immunodeficiency virus can be treated with a combination ofraltegravir, Truvada® and a compound described herein. In anotherembodiment, a host infected with human immunodeficiency virus can betreated with the combination of Complera® and a compound describedherein. It will be appreciated by one skilled in the art that a hostinfected with HIV can be treated with a number of combinations of drugsdepending on the mutation pattern of the virus. The patient can betreated with an appropriate combination of drugs in combination with acompound described herein.

In one embodiment, the host is infected with a hepatitis C virus and istreated with an anti-hepatitis C drug in addition to the active compounddescribed herein. For example, the patient can be treated with acombination of Sovaldi™, Harvoni®, ribavirin, and/or a pegylatedinterferon and a compound described herein. In one embodiment thepegylated interferon is PegIntron®. In another embodiment, the pegylatedinterferon is Pegasys®. In one embodiment, the host infected withhepatitis C virus is treated with Sovaldi™, ribavirin and a compounddescribed herein. In one embodiment, the host infected with hepatitis Cvirus is treated with Harvoni®, ribavirin and a compound describedherein. In one embodiment, a host infected with hepatitis C virus istreated with a combination of Olysio™, ribavirin, a pegylated interferonand a compound described herein. In one embodiment the pegylatedinterferon is PegIntron®. In another embodiment, the pegylatedinterferon is Pegasys®. In one embodiment, the host is infected with ahepatitis C virus and is treated with a combination of ABT-267, ABT-333and ABT-450/ritonavir, in addition to an active compound describedherein. In one embodiment, the host is infected with a hepatitis C virusand is treated with a combination of MK-5172 and MK-8742, in addition toan active compound described herein.

In one embodiment, a host infected with hepatitis C genotype 1 istreated with a combination of Sovaldi™, ribavirin, a pegylatedinterferon and a compound described herein for 12 weeks. In anotherembodiment, a host infected with hepatitis C genotype 1 is treated withSovaldi™ and a compound described herein for 12 weeks followed byribavirin, pegylated interferon and a compound described herein for 24weeks. In one embodiment, a host infected with hepatitis C genotype 2 istreated with Sovaldi™, ribavirin, and a compound described herein for 12weeks. In one embodiment, a host infected with hepatitis C genotype 3 istreated with Sovaldi™, ribavirin, and a compound described herein for 24weeks. In another embodiment, a host infected with hepatitis C genotype3 is treated with Sovaldi™, ribavirin, pegylated interferon, and acompound described herein for 12 weeks. In one embodiment, a hostinfected with hepatitis C genotype 4 is treated with Sovaldi™,ribavirin, pegylated interferon, and a compound described herein for 12weeks. In another embodiment, a host infected with hepatitis C genotype4 is treated with a combination of Olysio™, and a compound describedherein for 12 weeks followed by ribavirin, pegylated interferon and acompound described herein for 24-28 weeks.

In one embodiment, a host infected with hepatitis C genotype 5 istreated with Sovaldi™, ribavirin, pegylated interferon, and a compounddescribed herein for 12 weeks. In one embodiment, a host infected withhepatitis C genotype 5 is treated with ribavirin, pegylated interferon,and a compound described herein for 48 weeks. In one embodiment, a hostinfected with hepatitis C genotype 6 is treated with Sovaldi™,ribavirin, pegylated interferon, and a compound described herein for 12weeks. In one embodiment, a host infected with hepatitis C genotype 6 istreated with ribavirin, pegylated interferon, and a compound describedherein for 48 weeks.

In one embodiment, a host infected with hepatitis C genotype 1 istreated with Sovaldi™, Olysio™, ribavirin, and a compound describedherein for 12 weeks. In another embodiment, a host infected withhepatitis C genotype 1 is treated with Sovaldi™, ribavirin, and acompound described herein for 24 weeks. In one embodiment, a hostinfected with hepatitis C genotype 2 is treated with Sovaldi™,ribavirin, and a compound described herein for 12 weeks. In oneembodiment, a host infected with hepatitis C genotype 3 is treated withSovaldi™, ribavirin, and a compound described herein for 24 weeks. Inone embodiment, a patient infected with hepatitis C genotype 4 istreated with Sovaldi™, ribavirin, and a compound described herein for 24weeks.

In one embodiment, a host infected with papilloma virus is treated withimiquimod and a compound described herein. In another embodiment, a hostinfected with papilloma virus is treated with cryotherapy and a compounddescribed herein. In another embodiment, papilloma virus is surgicallyremoved from a host and the host is treated with a compound describedherein. In one embodiment, the host receives a compound described hereinprior to, during, and post-surgery. In one embodiment, the patientreceives a compound described herein post-surgery.

In one embodiment a host infected with herpes simplex type 2 is treatedwith Famvir® and a compound described herein. In one embodiment a hostinfected with herpes simplex type 1 is treated with acyclovir and acompound described herein. In another embodiment, a host infected withherpes simplex type 2 is treated with acyclovir and a compound describedherein. In one embodiment, a host infected with herpes simplex type 1 istreated with Valtrex® and a compound described herein. In anotherembodiment, a host infected with herpes simplex type 2 is treated withValtrex® and a compound described herein. In one embodiment, a hostinfected with herpes simplex type 1 virus receives a compound describedherein for 7 days prior to treatment with acyclovir. In one embodiment,a host infected with herpes simplex type 2 virus receives a compounddescribed herein for 7 days prior to treatment with acyclovir. In oneembodiment, a host infected with herpes simplex type 1 virus receives acompound described herein for 7 days prior to treatment with Valtrex®.In one embodiment, a host infected with herpes simplex type 2 virusreceives a compound described herein for 7 days prior to treatment withValtrex®.

In one embodiment a host infected with varicella zoster virus, VZV, istreated with acyclovir and a compound described herein. In anotherembodiment a host infected with varicella zoster virus, VZV, is treatedwith Valtrex® and a compound described herein. In one embodiment a hostinfected with varicella zoster virus, VZV, is treated with famciclovirand a compound described herein. In another embodiment a host infectedwith varicella zoster virus, VZV, is treated with foscarnet and acompound described herein. In one embodiment, a host infected withvaricella zoster virus is treated with a compound described herein priorto vaccination with Zostavax®. In another embodiment, a host infectedwith varicella zoster virus is treated with a compound described hereinprior to and post vaccination with Zostavax®.

In one embodiment a host infected with influenza virus is treated withRelenza® and a compound described herein. In another embodiment a hostinfected with influenza virus is treated with Tamiflu® and a compounddescribed herein. In another embodiment a host is infected withinfluenza virus and is treated with amantadine and a compound describedherein. In another embodiment, a host infected with influenza virus istreated with rimantadine and a compound described herein.

In one embodiment, a host infected with cytomegalovirus is treated withvalganciclovir and a compound described herein. In another embodiment, ahost infected with cytomegalovirus is treated with ganciclovir and acompound described herein. In one embodiment, a host infected withcytomegalovirus is treated with foscarnet and a compound describedherein. In another embodiment, a host infected with cytomegalovirus istreated with cidofovir and a compound described herein.

In one embodiment, a host infected with hepatitis B virus is treatedwith lamivudine and a compound described herein. In another embodiment,a host infected with hepatitis B virus is treated with adefovir and acompound described herein.

In one embodiment, a host infected with hepatitis B virus is treatedwith tenofovir and a compound described herein. In another embodiment, ahost infected with hepatitis B virus is treated with telbivudine and acompound described herein.

Bacterial Infections.

In one embodiment of the present invention, a compound of Formula I, II,III, or IV, or other active compound described herein, is used in aneffective amount to treat a host infected with a bacterial infection. Inone embodiment, the bacteria treated is, for example, a Gram-negative,bacilli (GNB), especially Escherichia coli, Gram-positive cocci (GPC),Staphylococcus aureus, Enterococcus faecalis, or Streptococcuspneumoniae. In one embodiment, the bacterial infection may be caused,for example, by a Gram-negative bacteria, including, but not limited toEscherichia coli, Salmonella, and other Enterobacteriaceae, Pseudomonas,Moraxella, Helicobacter, Stenotrophomonas, Bdellovibrio, acetic acidbacteria, Legionella, Staphylococcus aureus, Hemophilus influenzae,Klebsiella pneumoniae, Legionella pneumophila, Pseudomonas aeruginosa,Vibrio cholerae, Proteus mirabilis, Enterobacter cloacae, Serratiamarcescens, Clostridium tetani, Helicobacter pylori, Salmonellaenteritidis, Salmonella typhi, Shigella flexneri, or Acinetobacterbaumanii. In one embodiment, the bacterial infection may be caused, forexample, by a Gram-positive species from the following genera: Bacillus,Listeria, Staphylococcus, Enterococcus, Lactobacillus, Lactococcus,Leuconostoc, Pedicoccus, Streptococcus, Acetobacterium, Clostridium,Eubacterium, Heliobacterium, Heliospirillum, Megasphaera, Pectinatus,Selenomonas, Zymophilus, Sporomusa, Mycoplasma, Spiroplasma, Ureaplasma,or Erysipelothrix.

In one embodiment, the bacterial infection is associated with liverfailure. In one embodiment, an active compound disclosed herein isadministered in combination with an antibiotic or another anti-bacterialagent. In one embodiment, the compound administered is UNC2207A.

In one embodiment, the bacterial infection is associated with liverfailure. In one embodiment, an active compound disclosed herein isadministered in combination with an antibiotic or another anti-bacterialagent. In one embodiment, the compound administered is UNC2207A.

In one embodiment, a patient is suffering from acute-on-chronic liverfailure (ACLF). In one embodiment, a patient is suffering from acuteliver failure. In one embodiment, a patient is suffering from chronicliver failure. In one embodiment, the liver failure is caused by adisease or condition selected from alcoholic liver disease, chronicviral hepatitis type C, chronic viral hepatitis type B, chronic bileduct blockage, Wilson's disease, hemochromatosis, exposure to drug andtoxins, autoimmune hepatitis, cystic fibrosis, alpha antitrypsindeficiency, obesity or schistosomiasis.

In one embodiment, an active compound disclosed herein is administeredin combination with an antibiotic for the prevention or treatment ofbacterial infections. Examples of antibiotics include, but are notlimited to, cefotaxime (Claforan), ofloxacin (Floxin), norfloxacin(Noroxin) or trimethoprim/sulfamethoxazole (Bactrim, Septra).

5. Immunomodulatory and Immunostimulatory Agents

It has also been discovered that the compounds described herein can beused as immunomodulatory agents that reverse the MerTK-inducedsuppression of proinflammatory cytokines such as wound healing cytokines(IL-10 and GAS6) and enhance the expression of acute inflammatorycytokines (IL-12 and IL-6). In this way, the pyrazolopyrimidinecompounds can “re-normalize” or “re-program” the host microenvironmentin the diseased tissue area to attack the diseased cells. Thisimmunostimulatory activity can be used therapeutically to treat a hostwith a tumor, cancer or other neoplasm, or alternatively, to treat ahost with an infection, for example, a viral or bacterial infection.

Taking advantage of the immunostimulatory activity of the compoundsdescribed herein, or a pharmaceutically acceptable composition, salt,isotopic analog, or prodrug thereof, may be used for the treatment of aMERTK-negative (−/−) tumor or cancer. In one embodiment, the cancer is aMERTK-negative (−/−) breast cancer.

Therefore, as part of the invention, one or more of the compoundsdisclosed herein can be used as adjunctive therapy for itsimmunostimulatory effect as a means to increase the efficacy of theantineoplastic standard of care therapies, such as chemotherapeuticcompounds or radiation.

In another aspect of the invention, one or more of the compoundsdisclosed herein can be used as adjunctive therapy for itsimmunostimulatory effect as a means to increase the efficacy of theantiviral or antibacterial standard of care therapies.

For example, a compound of Formula I, II, III, or IV, or anothercompound as described herein, is administered to a host in animmunomodulatory effective amount to inhibit Mer tyrosine kinaseactivity in the host's tumor associated macrophage to suppress tumorimmunity. In one embodiment, the dosage of the Mer TKI administered asan immunomodulatory agent to stimulate innate anti-tumor immunity islower than a dosage of a Mer TKI administered to a host as a directanti-cancer agent. In one embodiment, the Mer TKI is administered at adosage which exhibits immunomodulatory but not direct cytotoxic effect.

In one embodiment, the cancer is a MERTK-negative (−/−) cancer. In oneembodiment, the MerTK inhibitory compound administered is UNC2207A.

Without wanting to be bound by any particular theory, it is believedthat the administration of a chemotherapeutic agent results in theapoptosis of tumor cells, exposing antigenic tumor proteins. The host'sinnate immune system is thus stimulated to recognize the antigenicapoptotic components from the tumor cells after chemotherapy or ionizingradiation and mount an immune response. In one embodiment, theadministration of a chemotherapeutic agent or ionizing radiation,before, with or subsequently followed by the administration of a Mer TKIis carried out using the normal standard of care chemotherapeuticprotocol. In another embodiment, the standard of care protocol of thechemotherapeutic is changed in a manner that causes less toxicity to thehost due to the adjunctive or synergistic activity of the Mer TKI.

In one embodiment, a method for the treatment of a tumor is providedthat includes administering an effective amount of a Mer TKI to inhibitTK signaling in a tumor associated macrophage, without inhibiting thesurvival signal in the tumor itself. In this way, the Mer TKI can beused to ramp up the immune response to the tumor by inhibitingmacrophage tumorogenic tolerance during normal tumor chemotherapeuticagent. The immunomodulatory dosage of the Mer TKI can be given prior to,with or after chemotherapeutic therapy and can be used simultaneouslywith or intermittently with the chemotherapeutic therapy. In oneembodiment, less chemotherapeutic therapy is needed than the normalstandard of care defined for that chemotherapeutic agent, due to theincreased efficacy of the immune response in the surrounding tumormicroenvironment. In one embodiment, a dose of Mer TKI including activecompounds of the present invention (for example 0.5 to 150 mg/dose) isgiven as a type of adjunctive therapy with the chemotherapeutic agent.

In one aspect of the invention, a Mer TKI is administered to a hosthaving a cancer as an immunomodulatory agent to inhibit Mer tyrosinekinase activity in a tumor associated macrophage in order to suppresstumor immunity. In one embodiment, the dosage of the Mer TKIadministered as an immunomodulatory agent to stimulate innate anti-tumorimmunity is lower than a dosage of a Mer TKI administered to a host as adirect anti-cancer agent. In one embodiment, the Mer TKI is administeredat a dosage which exhibits immunomodulatory but not direct cytotoxiceffects on the cancer.

In one embodiment, the dose associated with the immunomodulatory effectof an active compound of the present invention is about 2-fold, about3-fold, about 4-fold, about 5-fold, about 6-fold, about 7-fold, about8-fold, about 9-fold, about 10-fold or greater lower than the doseassociated with a direct survival-signal inhibiting anti-tumor orcytotoxic effect, or the direct antiviral or antibacterial effect. Inone embodiment, the dose used to induce an immunomodulatory effect in ahost is between about 0.5 mg and about 150 mg. In one embodiment, thedose is about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg,about 10 mg, about 12 mg, about 15 mg, about 20 mg, about 25 mg, about30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg,about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about85 mg, about 90 mg, about 95 mg, about 100 mg, about 110 mg, about 125mg, about 140 mg, or about 150 mg.

6. Anti-Tumor Agents, Including Anti-Cancer Agents

In one aspect of the invention, a compound of Formula I, II, III, or IV,or other active compound as described herein, is capable of directanti-cancer effects by inhibiting Mer tyrosine kinase within tumorcells. In one embodiment, the cancer treated overexpresses MerTK. In oneembodiment, the cancer which overexpresses MerTK is selected from thegroup consisting of acute myeloid leukemia, T-cell acute lymphoidleukemia, B-cell acute lymphoid leukemia, lung cancer, glioma, melanoma,prostate cancer, schwannoma, mantle cell lymphoma, and rhabdomyosarcoma.In an alternative embodiment, the cancer ectopically expresses MerTK. Inone embodiment, the compound administered is UNC2207A.

In one embodiment, the cancer treated has a mutation in the amino acidsequence of the MerTK extracellular or transmembrane domain selectedfrom P40S (melanoma), S159F (lung), E204K (urinary tract) S428G(gastric), I431F (lung), A446G (kidney), N454S (liver), W485S/C(lymphoma), and V486I (melanoma). In one embodiment the cancer treatedhas a mutation in the amino acid sequence of the MerTK cytosolic domainmutation selected from L586F (urinary tract), G594R (breast), S626C(urinary tract), P672S (lung), L688M (colon), A708S (head and neck),N718Y (lung), R722stop (colon), M790V (lung), P802S (melanoma), V873I(liver), S905F (lung), K923R (melanoma), P958L (kidney), D983N (liver),and D990N (colon). In one embodiment, the compound administered isUNC2207A.

In one embodiment of the invention, a compound of Formula I, II, III, orIV, as described herein, is administered to a host with a cancer incombination with one or more additional chemotherapeutic agents,resulting in a synergistic anti-cancer effect and the prolonged survivalof a host compared to treatment with either a compound described hereinor chemotherapeutic agent alone. In one embodiment, the use of a MerTKIcompound described herein in combination with a chemotherapeutic agentprovides for increased anti-tumor effects without an increase in thestandard of care dosage of the chemotherapeutic agent. In oneembodiment, the use of a MerTKI compound described herein in combinationwith a chemotherapeutic provides for equivalent or increased anti-tumoreffects utilizing a lower dosage of a chemotherapeutic agent than thestandard of care dosage.

In one embodiment, a compound of Formula I, II, III, or IV, as describedherein, is provided for use in treating a non-small cell lung carcinoma(NSCLC). In one embodiment, a method is provided to treat a host withnon-small cell lung carcinoma (NSCLC) comprising administering to thehost an effective amount of a compound of Formula I, II, III, or IV incombination with one or more additional chemotherapeutic agents. In oneembodiment of the invention, a method is provided to treat a host withcancer comprising administering to the host an effective amount of a MerTKI including active compounds of the present invention in combinationwith another tyrosine kinase inhibitor. In one embodiment, the tyrosinekinase inhibitor is a fibroblast growth factor receptor (FGFR)inhibitor. In one embodiment, the FGFR inhibitor is AZD-4547. In oneembodiment, the cancer is non-small cell lung carcinoma (NSCLC). In someembodiments of the invention, a method is provided to treat a host withnon-small cell lung carcinoma (NSCLC) comprising administering to thehost an effective amount of a Mer TKI including active compounds of thepresent invention in combination with an additional tyrosine kinaseinhibitor, wherein the Mer TKI is selected from the group consisting ofUNC2207A, and wherein the additional tyrosine kinase inhibitor isselected from the group consisting of gefitinib and crizotinib.

In one embodiment, a compound of Formula I, II, III, or IV, as describedherein, is provided for use in treating a melanoma. In one embodiment,the administration of the Mer TKI compound described herein is combinedwith a chemotherapeutic agent. In one embodiment, the chemotherapeuticagent is an anti-programmed cell death-1 (PD-1) agent. In oneembodiment, the chemotherapeutic agent is a B-RAF inhibitor. In oneembodiment, the B-RAF inhibitor is vemurafenib. In one embodiment, thehost does not have a melanoma with a B-RAF mutation. In one embodiment,the host has a melanoma with a B-RAF mutation. In one embodiment, thehost has a melanoma with a RAS mutation. In one embodiment, the melanomaover-expresses MerTK. In one embodiment, the melanoma has metastasized.In one embodiment, the MerTK inhibitory compound administered isUNC2207A.

In one embodiment, a compound of Formula I, II, III, or IV, as describedherein, is provided for use in treating Acute Lymphoblastic Leukemia(ALL). In one embodiment, a method is provided to treat a host with ALLcomprising administering to the host an effective amount of a compoundof Formula I, II, III, or IV in combination with methotrexate. In oneembodiment, the MerTK inhibitory compound administered is UNC2207A.

In one embodiment, a compound of Formula I, II, III, or IV, as describedherein, is provided for use in treating Acute Myeloid Leukemia (AML). Inone embodiment, the AML contains a wild type FLT3 protein. In oneembodiment, the replication of the AML cells are dependent on FLT3expression. In one embodiment, the AML contains a FLT3-ITD mutation. Inone embodiment, the AML contains a FLT3-TKD mutation. In one embodiment,the AML contains both a FLT3-ITD and FLT3-TKD mutation. In oneembodiment, a FLT3 or dual MER/FLT3 inhibitor described herein isadministered to a host suffering from AML, wherein the AML contains amutation within the FLT3-TKD at amino acid F691 or D835. In oneembodiment, the MerTK inhibitory compound administered is UNC2207A.

In one embodiment, a tumor survival-signal inhibiting amount (forexample 0.5 to 150 mg/dose) of Mer TKI including compounds of thepresent invention is administered to a host alone or in combination witha chemotherapeutic agent and/or anti-cancer targeted agent. In analternative embodiment, a tumor survival-signal inhibiting amount (forexample, at least 150 mg/dose, and in some embodiments, at least 200,250, 300, 350, 400, 450, or 500 mg/dosage or more) of Mer TKI includingactive compounds of the present invention is administered to a hostalone or in combination with a chemotherapeutic agent and/or anti-cancertargeted agent. In one embodiment, the Mer TKI and the chemotherapeuticagent act synergistically. In one embodiment, the use of a Mer TKI incombination with a chemotherapeutic agent provides for increasedanti-tumor effects without an increase in the standard of care dosage ofthe chemotherapeutic agent.

In one embodiment, the use of a Mer TKI including compounds of thepresent invention in combination with a chemotherapeutic provides forequivalent or increased anti-tumor effects utilizing a lower dosage of achemotherapeutic agent than the standard of care dosage.

In one aspect of the invention, the Mer TKI including compounds of thepresent invention can be administered to a host with a cancer prior to,during, or after administration with a chemotherapeutic agent orexposure to ionizing radiation. In one embodiment, a host isadministered an effective amount of a chemotherapeutic agent or ionizingradiation and subsequently administered a Mer TKI.

In one embodiment, a method is provided to treat a host with cancercomprising administering to the host an effective amount of a compoundof Formula I, II, III, or IV in combination with an immunomodulatoryagent. In one embodiment, the immunomodulatory agent is selected fromthe group consisting of a CTLA-4 inhibitor, PD-1 or anti-PD-1 ligand,IFN-alpha, IFN-beta, and a vaccine, for example, a cancer vaccine. Inone embodiment, a method is provided to treat a host with cancercomprising administering to the host an effective amount of a Mer TKIincluding active compounds of the present invention in combination withKeytruda® (pembrolizumab). In one embodiment, a method is provided totreat a host with cancer comprising administering to the host aneffective amount of a Mer TKI including active compounds of the presentinvention in combination with Opdivo (nivolumab). In one embodiment, amethod is provided to treat a host with cancer comprising administeringto the host an effective amount of a Mer TKI including active compoundsof the present invention in combination with Yervoy® (ipilimumab). Insome embodiments, a method is provided to treat a host with cancercomprising administering to the host an effective amount of a Mer TKIincluding active compounds of the present invention in combination withan immunomodulatory agent selected from the group consisting ofpembrolizumab and ipilimumab, wherein the Mer TKI is selected from thegroup consisting of UNC2207A, wherein the cancer is melanoma.

In one embodiment, the Mer TKIs useful in the present invention,including active compounds of the present invention, are dual MER/FLT-3TKIs. In one embodiment, the Mer TKIs are dual MER/Axl TKIs. In oneembodiment, the Mer TKIs are MER-specific TKIs.

Tumors.

The active compounds and methods described herein are useful for thetreatment of tumors. As contemplated herein, the cancer treated can be aprimary tumor or a metastatic tumor. In one aspect, the methodsdescribed herein are used to treat a solid tumor, for example, melanoma,lung cancer (including lung adenocarcinoma, basal cell carcinoma,squamous cell carcinoma, large cell carcinoma, bronchioloalveolarcarcinoma, bronchiogenic carcinoma, non-small-cell carcinoma, small cellcarcinoma, mesothelioma); breast cancer (including ductal carcinoma,lobular carcinoma, inflammatory breast cancer, clear cell carcinoma,mucinous carcinoma, serosal cavities breast carcinoma); colorectalcancer (colon cancer, rectal cancer, colorectal adenocarcinoma); analcancer; pancreatic cancer (including pancreatic adenocarcinoma, isletcell carcinoma, neuroendocrine tumors); prostate cancer; prostateadenocarcinoma; ovarian carcinoma (ovarian epithelial carcinoma orsurface epithelial-stromal tumor including serous tumor, endometrioidtumor and mucinous cystadenocarcinoma, sex-cord-stromal tumor); liverand bile duct carcinoma (including hepatocellular carcinoma,cholangiocarcinoma, hemangioma); esophageal carcinoma (includingesophageal adenocarcinoma and squamous cell carcinoma); oral andoropharyngeal squamous cell carcinoma; salivary gland adenoid cysticcarcinoma; bladder cancer; bladder carcinoma; carcinoma of the uterus(including endometrial adenocarcinoma, ocular, uterine papillary serouscarcinoma, uterine clear-cell carcinoma, uterine sarcomas andleiomyosarcomas, mixed mullerian tumors); glioma, glioblastoma,medullablastoma, and other tumors of the brain; kidney cancers(including renal cell carcinoma, clear cell carcinoma, Wilm's tumor);cancer of the head and neck (including squamous cell carcinomas); cancerof the stomach (gastric cancers, stomach adenocarcinoma,gastrointestinal stromal tumor); testicular cancer; germ cell tumor;neuroendocrine tumor; cervical cancer; carcinoids of thegastrointestinal tract, breast, and other organs; signet ring cellcarcinoma; mesenchymal tumors including sarcomas, fibrosarcomas,haemangioma, angiomatosis, haemangiopericytoma, pseudoangiomatousstromal hyperplasia, myofibroblastoma, fibromatosis, inflammatorymyofibroblastic tumor, lipoma, angiolipoma, granular cell tumor,neurofibroma, schwannoma, angiosarcoma, liposarcoma, rhabdomyosarcoma,osteosarcoma, leiomyoma, leiomysarcoma, skin, including melanoma,cervical, retinoblastoma, head and neck cancer, pancreatic, brain,thyroid, testicular, renal, bladder, soft tissue, adenal gland, urethra,cancers of the penis, myxosarcoma, chondro sarcoma, osteosarcoma,chordoma, malignant fibrous histiocytoma, lymphangiosarcoma,mesothelioma, squamous cell carcinoma; epidermoid carcinoma, malignantskin adnexal tumors, adenocarcinoma, hepatoma, hepatocellular carcinoma,renal cell carcinoma, hypernephroma, cholangiocarcinoma, transitionalcell carcinoma, choriocarcinoma, seminoma, embryonal cell carcinoma,glioma anaplastic; glioblastoma multiforme, neuroblastoma,medulloblastoma, malignant meningioma, malignant schwannoma, neurofibrosarcoma, parathyroid carcinoma, medullary carcinoma of thyroid,bronchial carcinoid, pheochromocytoma, Islet cell carcinoma, malignantcarcinoid, malignant paraganglioma, melanoma, Merkel cell neoplasm,cystosarcoma phylloide, salivary cancers, thymic carcinomas, and cancersof the vagina among others.

In some embodiments, a method is provided to treat a host with aglioblastoma comprising administering to the host an effective amount ofa Mer TKI including active compounds of the present invention incombination with temozolomide, wherein the Mer TKI is selected from thegroup consisting of UNC2207A. In some embodiments, a method is providedto treat a host with a breast cancer comprising administering to thehost an effective amount of a Mer TKI including active compounds of thepresent invention in combination with trastuzumab, wherein the Mer TKIis selected from the group consisting of UNC2207A.

In one embodiment, the cancer is NSCLC. In one embodiment, the cancer isa melanoma. In one embodiment, the cancer is breast cancer. In oneembodiment, the cancer is a glioblastoma. In one embodiment, the canceris a bone cancer. In one embodiment, the cancer is a brain cancer. Inone embodiment, the cancer is a colon cancer. In one embodiment, thecancer is a rectal cancer. In one embodiment, the cancer is anendometrial cancer. In one embodiment, the cancer is an esophagealcancer. In one embodiment, the cancer is a cancer of thegastrointestinal tract. In one embodiment, the cancer is a kidneycancer. In one embodiment, the cancer is a liver cancer. In oneembodiment, the cancer is a lung cancer. In one embodiment, the canceris a mantle cell lymphoma. In one embodiment, the cancer is an ovariancancer. In one embodiment, the cancer is a pancreatic cancer. In oneembodiment, the cancer is a pituitary cancer. In one embodiment, thecancer is a prostate cancer. In one embodiment, the cancer is a skeletalmuscle cancer. In one embodiment, the cancer is a skin cancer. In oneembodiment, the cancer is a stomach cancer. In one embodiment, thecancer is a thyroid cancer. In one embodiment, the cancer is aneuroendocrine cancer. In one embodiment, the cancer is agastroesophageal cancer. In one embodiment, the cancer is a renal cellcancer. In one embodiment, the cancer is a head and neck cancer. In someembodiments, the Mer TKI used to treat a host having a cancer isselected from the group consisting of UNC2207A.

In one embodiment, the methods described herein are useful for treatinga host suffering from a lymphoma or lymphocytic or myelocyticproliferation disorder or abnormality. For example, the Mer TKIs asdescribed herein can be administered to a subject suffering from aHodgkin Lymphoma of a Non-Hodgkin Lymphoma. For example, the subject canbe suffering from a Non-Hodgkin Lymphoma such as, but not limited to: anAIDS-Related Lymphoma; Anaplastic Large-Cell Lymphoma;Angioimmunoblastic Lymphoma; Blastic NK-Cell Lymphoma; Burkitt'sLymphoma; Burkitt-like Lymphoma (Small Non-Cleaved Cell Lymphoma);Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma; CutaneousT-Cell Lymphoma; Diffuse Large B-Cell Lymphoma; Enteropathy-Type T-CellLymphoma; Follicular Lymphoma; Hepatosplenic Gamma-Delta T-CellLymphoma; Lymphoblastic Lymphoma; Mantle Cell Lymphoma; Marginal ZoneLymphoma; Nasal T-Cell Lymphoma; Pediatric Lymphoma; Peripheral T-CellLymphomas; Primary Central Nervous System Lymphoma; T-Cell Leukemias;Transformed Lymphomas; Treatment-Related T-Cell Lymphomas; orWaldenstrom's Macroglobulinemia.

Alternatively, the subject may be suffering from a Hodgkin Lymphoma,such as, but not limited to: Nodular Sclerosis Classical Hodgkin'sLymphoma (CHL); Mixed Cellularity CHL; Lymphocyte-depletion CHL;Lymphocyte-rich CHL; Lymphocyte Predominant Hodgkin Lymphoma; or NodularLymphocyte Predominant HL.

In one embodiment, the methods as described herein may be useful totreat a host suffering from a specific T-cell, a B-cell, or a NK-cellbased lymphoma, proliferative disorder, or abnormality. For example, thesubject can be suffering from a specific T-cell or NK-cell lymphoma, forexample, but not limited to: Peripheral T-cell lymphoma, for example,peripheral T-cell lymphoma and peripheral T-cell lymphoma not otherwisespecified (PTCL-NOS); anaplastic large cell lymphoma, for exampleanaplastic lymphoma kinase (ALK) positive, ALK negative anaplastic largecell lymphoma, or primary cutaneous anaplastic large cell lymphoma;angioimmunoblastic lymphoma; cutaneous T-cell lymphoma, for examplemycosis fungoides, Sézary syndrome, primary cutaneous anaplastic largecell lymphoma, primary cutaneous CD30+ T-cell lymphoproliferativedisorder; primary cutaneous aggressive epidermotropic CD8+ cytotoxicT-cell lymphoma; primary cutaneous gamma-delta T-cell lymphoma; primarycutaneous small/medium CD4+ T-cell lymphoma. and lymphomatoid papulosis;Adult T-cell Leukemia/Lymphoma (ATLL); Blastic Lymphoma;Enteropathy-type T-cell lymphoma; Hematosplenic gamma-delta T-cellLymphoma; Lymphoblastic Lymphoma; Nasal NK/T-cell Lymphomas;Treatment-related T-cell lymphomas; for example lymphomas that appearafter solid organ or bone marrow transplantation; T-cell prolymphocyticleukemia; T-cell large granular lymphocytic leukemia; Chroniclymphoproliferative disorder of NK-cells; Aggressive NK cell leukemia;Systemic EBV+ T-cell lymphoproliferative disease of childhood(associated with chronic active EBV infection); Hydroa vacciniforme-likelymphoma; Adult T-cell leukemia/lymphoma; Enteropathy-associated T-celllymphoma; Hepatosplenic T-cell lymphoma; or Subcutaneouspanniculitis-like T-cell lymphoma.

Alternatively, the subject may be suffering from a specific B-celllymphoma or proliferative disorder such as, but not limited to: multiplemyeloma; Diffuse large B cell lymphoma; Follicular lymphoma;Mucosa-Associated Lymphatic Tissue lymphoma (MALT); Small celllymphocytic lymphoma; Mantle cell lymphoma (MCL); Burkitt lymphoma;Mediastinal large B cell lymphoma; Waldenström macroglobulinemia; Nodalmarginal zone B cell lymphoma (NMZL); Splenic marginal zone lymphoma(SMZL); Intravascular large B-cell lymphoma; Primary effusion lymphoma;or Lymphomatoid granulomatosis; Chronic lymphocytic leukemia/smalllymphocytic lymphoma; B-cell prolymphocytic leukemia; Hairy cellleukemia; Splenic lymphoma/leukemia, unclassifiable; Splenic diffuse redpulp small B-cell lymphoma; Hairy cell leukemia-variant;Lymphoplasmacytic lymphoma; Heavy chain diseases, for example, Alphaheavy chain disease, Gamma heavy chain disease, Mu heavy chain disease;Plasma cell myeloma; Solitary plasmacytoma of bone; Extraosseousplasmacytoma; Primary cutaneous follicle center lymphoma; Tcell/histiocyte rich large B-cell lymphoma; DLBCL associated withchronic inflammation; Epstein-Barr virus (EBV)+ DLBCL of the elderly;Primary mediastinal (thymic) large B-cell lymphoma; Primary cutaneousDLBCL, leg type; ALK+ large B-cell lymphoma; Plasmablastic lymphoma;Large B-cell lymphoma arising in HHV8-associated multicentric; Castlemandisease; B-cell lymphoma, unclassifiable, with features intermediatebetween diffuse large B-cell lymphoma and Burkitt lymphoma; B-celllymphoma, unclassifiable, with features intermediate between diffuselarge B-cell lymphoma and classical Hodgkin lymphoma; Nodular sclerosisclassical Hodgkin lymphoma; Lymphocyte-rich classical Hodgkin lymphoma;Mixed cellularity classical Hodgkin lymphoma; or Lymphocyte-depletedclassical Hodgkin lymphoma.

In one embodiment, the methods described herein can be used to a subjectsuffering from a leukemia. For example, the subject may be sufferingfrom an acute or chronic leukemia of a lymphocytic or myelogenousorigin, such as, but not limited to: Acute lymphoblastic leukemia (ALL);Acute myelogenous leukemia (AML); Chronic lymphocytic leukemia (CLL);Chronic myelogenous leukemia (CML); juvenile myelomonocytic leukemia(JMML); hairy cell leukemia (HCL); acute promyelocytic leukemia (asubtype of AML); T-cell prolymphocytic leukemia (TPLL); large granularlymphocytic leukemia; or Adult T-cell chronic leukemia; large granularlymphocytic leukemia (LGL). In one embodiment, the patient suffers froman acute myelogenous leukemia, for example an undifferentiated AML (M0);myeloblastic leukemia (M1; with/without minimal cell maturation);myeloblastic leukemia (M2; with cell maturation); promyelocytic leukemia(M3 or M3 variant [M3V]); myelomonocytic leukemia (M4 or M4 variant witheosinophilia [M4E]); monocytic leukemia (M5); erythroleukemia (M6); ormegakaryoblastic leukemia (M7).

Acute Myeloid Leukemia.

In one embodiment, the methods described herein can be used to treat ahost suffering from Acute Myeloid Leukemia (AML). In one embodiment, theAML contains a wild type FLT3 protein. In one embodiment, thereplication of the AML cells are dependent on FLT3 expression. In oneembodiment, the AML contains a FLT3-ITD mutation. In one embodiment, theAML contains a FLT3-TKD mutation. In one embodiment, the AML containsboth a FLT3-ITD and FLT3-TKD mutation.

FLT3-ITD mutations are well known in the art. FLT3-TKD mutations arealso well known in the art. In one embodiment, a FLT3 or dual MER/FLT3inhibitor is administered to a host suffering from AML, wherein the AMLcontains a mutation within the FLT3-TKD at amino acid F691 or D835. Inone embodiment, the FLT3-TKD mutation is selected from D835H, D835N,D835Y, D835A, D835V, D835V, D835E, I836F, I836L, 1836V, I836D, I836H,I836M, and F691L. In one embodiment, the host is suffering from theFLT3-TKD mutation D835Y. In one embodiment, the host is suffering fromthe FLT3-TKD mutation F691L.

In one embodiment, the host is suffering from acute promyelocyticleukemia (a subtype of AML); a minimally differentiated AML (M0);myeloblastic leukemia (M1; with/without minimal cell maturation);myeloblastic leukemia (M2; with cell maturation); promyelocytic leukemia(M3 or M3 variant [M3V]); myelomonocytic leukemia (M4 or M4 variant witheosinophilia [M4E]); monocytic leukemia (M5); erythroleukemia (M6); ormegakaryocytic leukemia (M7). In one embodiment, the host is sufferingfrom AML that has relapsed or become refractory to previous treatments.In one embodiment, the host has previously been treated with a FLT3inhibitor or other chemotherapeutic agent.

In one embodiment, the FLT3 inhibitors are efficacious against AMLhaving both FLT3-ITD and FLT3-TKD mutations, wherein resistance to otherFLT3 inhibitors, for example, AC220, has been established.

In one embodiment, the host has an Acute Myeloid Leukemia (AML)comprising a FLT3 mutation, wherein the mutation confers resistance to aFLT3 inhibitor other than the FLT3 inhibitors described herein. In oneembodiment, the host has a AML comprising a FLT3 mutation, wherein themutation has conferred resistance to quizartinib (AC220) or other FLT3inhibitor selected from lestaurtinib, sunitinib, sorafenib, tandutinib,midostaurin, amuvatinib crenolanib, dovitinib, ENMD-2076 (Entremed), orKW-2449 (Kyowa Hakko Kirin), or a combination thereof.

Chemotherapeutic Agents.

In one embodiment, an active compound or Mer TKI as described herein isused in combination or alternation with a chemotherapeutic agent. Suchagents may include, but are not limited to, tamoxifen, midazolam,letrozole, bortezomib, anastrozole, goserelin, an mTOR inhibitor, a PI3kinase inhibitors, dual mTOR-PI3K inhibitors, MEK inhibitors, RASinhibitors, ALK inhibitors, HSP inhibitors (for example, HSP70 and HSP90 inhibitors, or a combination thereof). Examples of mTOR inhibitorsinclude but are not limited to rapamycin and its analogs, everolimus(Afinitor), temsirolimus, ridaforolimus, sirolimus, and deforolimusExamples of P13 kinase inhibitors include but are not limited toWortmannin, demethoxyviridin, perifosine, idelalisib, PX-866, IPI-145,BAY 80-6946, BEZ235, RP6503, TGR 1202 (RP5264), MLN1117 (INK1117),Pictilisib, Buparlisib, SAR245408 (XL147), SAR245409 (XL765), Palomid529, ZSTK474, PWT33597, RP6530, CUDC-907, and AEZS-136. Examples of MEKinhibitors include but are not limited to Tametinib, Selumetinib,MEK162, GDC-0973 (XL518), and PD0325901. Examples of RAS inhibitorsinclude but are not limited to Reolysin and siG12D LODER. Examples ofALK inhibitors include but are not limited to Crizotinib, AP26113, andLDK378. HSP inhibitors include but are not limited to Geldanamycin or17-N-Allylamino-17-demethoxygeldanamycin (17AAG), and Radicicol. In oneembodiment, the chemotherapeutic agent is an anti-programmed celldeath-1 (PD-1) agent, for example, nivolumab, pembrolizumab, BMS936559,lambrolizumab, MPDL3280A, pidilizumab, AMP-244, and MEDI4736. In oneembodiment, the chemotherapeutic agent is a B-RAF inhibitor, forexample, vemurafenib or sorafenib. In one embodiment, thechemotherapeutic agent is a FGFR inhibitor, for example, but not limitedto, AZD4547, dovitinib, BGJ398, LY2874455, and ponatinib. In oneembodiment, an active compound or Mer TKI as described herein is used incombination with crizotinib.

In certain aspects, the additional therapeutic agent is ananti-inflammatory agent, a chemotherapeutic agent, a radiotherapeutic,an additional therapeutic agent, or an immunosuppressive agent.

Suitable chemotherapeutic agents include, but are not limited to,radioactive molecules, toxins, also referred to as cytotoxins orcytotoxic agents, which includes any agent that is detrimental to theviability of cells, agents, and liposomes or other vesicles containingchemotherapeutic compounds. General anticancer pharmaceutical agentsinclude: Vincristine (Oncovin®) or liposomal vincristine (Marqibo®),Daunorubicin (daunomycin or Cerubidine®) or doxorubicin (Adriamycin®),Cytarabine (cytosine arabinoside, ara-C, or Cytosar®), L-asparaginase(Elspar®) or PEG-L-asparaginase (pegaspargase or Oncaspar®), Etoposide(VP-16), Teniposide (Vumon®), 6-mercaptopurine (6-MP or Purinethol®),Methotrexate, Cyclophosphamide (Cytoxan®), Prednisone, Dexamethasone(Decadron), imatinib (Gleevec®), dasatinib (Sprycel®), nilotinib(Tasigna®), bosutinib (Bosulif®), and ponatinib (Iclusig™). Examples ofadditional suitable chemotherapeutic agents include but are not limitedto 1-dehydrotestosterone, 5-fluorouracil decarbazine, 6-mercaptopurine,6-thioguanine, actinomycin D, adriamycin, aldesleukin, alkylatingagents, allopurinol sodium, altretamine, amifostine, anastrozole,anthramycin (AMC)), anti-mitotic agents, cis-dichlorodiamine platinum(II) (DDP) cisplatin), diamino dichloro platinum, anthracyclines,antibiotics, antimetabolites, asparaginase, BCG live (intravesical),betamethasone sodium phosphate and betamethasone acetate, bicalutamide,bleomycin sulfate, busulfan, calcium leucouorin, calicheamicin,capecitabine, carboplatin, lomustine (CCNU), carmustine (BSNU),Chlorambucil, Cisplatin, Cladribine, Colchicin, conjugated estrogens,Cyclophosphamide, Cyclothosphamide, Cytarabine, Cytarabine, cytochalasinB, Cytoxan, Dacarbazine, Dactinomycin, dactinomycin (formerlyactinomycin), daunirubicin HCL, daunorucbicin citrate, denileukindiftitox, Dexrazoxane, Dibromomannitol, dihydroxy anthracin dione,Docetaxel, dolasetron mesylate, doxorubicin HCL, dronabinol, E. coliL-asparaginase, emetine, epoetin-α, Erwinia L-asparaginase, esterifiedestrogens, estradiol, estramustine phosphate sodium, ethidium bromide,ethinyl estradiol, etidronate, etoposide citrororum factor, etoposidephosphate, filgrastim, floxuridine, fluconazole, fludarabine phosphate,fluorouracil, flutamide, folinic acid, gemcitabine HCL, glucocorticoids,goserelin acetate, gramicidin D, granisetron HCL, hydroxyurea,idarubicin HCL, ifosfamide, interferon α-2b, irinotecan HCL, letrozole,leucovorin calcium, leuprolide acetate, levamisole HCL, lidocaine,lomustine, maytansinoid, mechlorethamine HCL, medroxyprogesteroneacetate, megestrol acetate, melphalan HCL, mercaptipurine, mesna,methotrexate, methyltestosterone, mithramycin, mitomycin C, mitotane,mitoxantrone, nilutamide, octreotide acetate, oligomycin A, ondansetronHCL, paclitaxel, pamidronate disodium, pentostatin, pilocarpine HCL,plimycin, polifeprosan 20 with carmustine implant, porfimer sodium,procaine, procarbazine HCL, propranolol, rituximab, sargramostim,streptozotocin, tamoxifen, taxol, teniposide, tenoposide, testolactone,tetracaine, thioepa chlorambucil, thioguanine, thiotepa, topotecan HCL,toremifene citrate, trastuzumab, tretinoin, valrubicin, vinblastinesulfate, vincristine sulfate, and vinorelbine tartrate. In oneembodiment, an active compound or Mer TKI as described herein is used incombination with oligomycin A.

Additional therapeutic agents that can be administered in combinationwith a compound disclosed herein can include bevacizumab, sutinib,sorafenib, 2-methoxyestradiol or 2ME2, finasunate, vatalanib,vandetanib, aflibercept, volociximab, etaracizumab (MEDI-522),cilengitide, erlotinib, cetuximab, panitumumab, gefitinib, trastuzumab,dovitinib, figitumumab, atacicept, rituximab, alemtuzumab, aldesleukine,atlizumab, tocilizumab, temsirolimus, everolimus, lucatumumab,dacetuzumab, HLL1, huN901-DM1, atiprimod, natalizumab, bortezomib,carfilzomib, marizomib, tanespimycin, saquinavir mesylate, ritonavir,nelfinavir mesylate, indinavir sulfate, belinostat, panobinostat,mapatumumab, lexatumumab, dulanermin, ABT-737, oblimersen, plitidepsin,talmapimod, P276-00, enzastaurin, tipifarnib, perifosine, imatinib,dasatinib, lenalidomide, thalidomide, simvastatin, ABT-888,temozolomide, erlotinib, lapatinib, sunitinib, FTS, AZD6244, BEZ235, andcelecoxib. In one embodiment, an active compound or Mer TKI as describedherein is used in combination with gefitinib.

In one embodiment, a FLT3 or dual MER/FLT3 inhibitor described herein isused in combination with a chemotherapeutic agent for the treatment ofAML. Such agents may include, but are not limited to, cytarabine(ara-C), anthracycline drugs including but not limited to, daunorubicin,idarubicin; cladribine, fludarabine, Gleevec® (imatinib), Sprycel®(dasatinib), adriamycin, arsenic trioxide, cerubidine, clafen,cyclophosphamide, cytarabine, daunorubicin, doxorubicin, vincristine,and topotecan. Some of the other chemo drugs that may be used to treatAML include: etoposide (VP-16), 6-thioguanine (6-TG), hydroxyurea(Hydrea®), Corticosteroid drugs, such as prednisone or dexamethasone(Decadron®), methotrexate (MTX), 6-mercaptopurine (6-MP), azacitidine(Vidaza®), and decitabine (Dacogen®). In one embodiment, a FLT3 or dualMER/FLT3 inhibitor described herein is used in combination withcytarabine.

In one embodiment, a FLT3 or dual MER/FLT3 inhibitor described herein isused in combination with an additional FLT3 inhibitor to treat with ahost suffering from AML. Additional FLT3 inhibitors for use incombination with the FLT3 or dual MER/FLT3 inhibitors described hereininclude lestaurtinib, sunitinib, sorafenib, tandutinib, midostaurin,crenolanib, dovitinib, ENMD-2076 (Entremed), amuvatinib, or KW-2449(Kyowa Hakko Kirin).

In one embodiment, a FLT3 or dual MER/FLT3 inhibitor described herein isused in combination with a Ras inhibitor. Examples of RAS inhibitorsinclude but are not limited to Reolysin, FusOn-H2, and siG12D LODER.

In one embodiment, a FLT3 or dual MER/FLT3 inhibitor described herein isused in combination with a Phosphoinositide 3-kinase inhibitor (PI3Kinhibitor). PI3K inhibitors that may be used in the present inventionare well known. Examples of PI3K inhibitors include but are not limitedto Wortmannin, demethoxyviridin, perifosine, idelalisib, Pictilisib,Palomid 529, ZSTK474, PWT33597, CUDC-907, AEZS-136, PX-866, IPI-145,RP6503, SAR245408 (XL147), duvelisib, GS-9820, GDC-0032(2-[4-[2-(2-Isopropyl-5-methyl-1,2,4-triazol-3-yl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepin-9-yl]pyrazol-1-yl]-2-methylpropanamide),MLN-1117 ((2R)-1-Phenoxy-2-butanyl hydrogen (S)-methylphosphonate; orMethyl(oxo) {[(2R)-1-phenoxy-2-butanyl]oxy}phosphonium)), BYL-719((2S)—N1-[4-Methyl-5-[2-(2,2,2-trifluoro-1,1-dimethylethyl)-4-pyridinyl]-2-thiazolyl]-1,2-pyrrolidinedicarboxamide),GSK2126458(2,4-Difluoro-N-{2-(methyloxy)-5-[4-(4-pyridazinyl)-6-quinolinyl]-3-pyridinyl}benzenesulfonamide),TGX-221((±)-7-Methyl-2-(morpholin-4-yl)-9-(1-phenylaminoethyl)-pyrido[1,2-a]-pyrimidin-4-one),GSK2636771(2-Methyl-1-(2-methyl-3-(trifluoromethyl)benzyl)-6-morpholino-1H-benzo[d]imidazole-4-carboxylicacid dihydrochloride), KIN-193((R)-2-((1-(7-methyl-2-morpholino-4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl)ethyl)amino)benzoicacid), TGR-1202/RP5264, GS-9820((S)-1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-mohydroxypropan-1-one),GS-1101(5-fluoro-3-phenyl-2([S)]-1-[9H-purin-6-ylamino]-propyl)-3H-quinazolin-4-one),AMG-319, GSK-2269557, SAR245409(N-(4-(N-(3-((3,5-dimethoxyphenyl)amino)quinoxalin-2-yl)sulfamoyl)phenyl)-3-methoxy-4methylbenzamide), BAY80-6946(2-amino-N-(7-methoxy-8-(3-morpholinopropoxy)-2,3-dihydroimidazo[1,2-c]quinaz),AS 252424(5-[1-[5-(4-Fluoro-2-hydroxy-phenyl)-furan-2-yl]-meth-(Z)-ylidene]-thiazolidine-2,4-dione),CZ 24832(5-(2-amino-8-fluoro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-N-tert-butylpyridine-3-sulfonamide),Buparlisib(5-[2,6-Di(4-morpholinyl)-4-pyrimidinyl]-4-(trifluoromethyl)-2-pyridinamine),GDC-0941(2-(1H-Indazol-4-yl)-6-[[4-(methylsulfonyl)-1-piperazinyl]methyl]-4-(4-morpholinyl)thieno[3,2-d]pyrimidine),GDC-0980((S)-1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one (also known as RG7422)),SF1126((8S,14S,17S)-14-(carboxymethyl)-8-(3-guanidinopropyl)-17-(hydroxymethyl)-3,6,9,12,15-pentaoxo-1-(4-(4-oxo-8-phenyl-4H-chromen-2-yl)morpholino-4-ium)-2-oxa-7,10,13,16-tetraazaoctadecan-18-oate), PF-05212384(N-[4-[[4-(Dimethylamino)-1-piperidinyl]carbonyl]phenyl]-N′-[4-(4,6-di-4-morpholinyl-1,3,5-triazin-2-yl)phenyl]urea),LY3023414, BEZ235(2-Methyl-2-{4-[3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl]phenyl}propanenitrile),XL-765(N-(3-(N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)sulfamoyl)phenyl)-3-methoxy-4-methylbenzamide),and GSK1059615(5-[[4-(4-Pyridinyl)-6-quinolinyl]methylene]-2,4-thiazolidenedione),PX886([(3aR,6E,9S,9aR,10R,11aS)-6-[[bis(prop-2-enyl)amino]methylidene]-5-hydroxy-9-(methoxymethyl)-9a,11a-dimethyl-1,4,7-trioxo-2,3,3a,9,10,11-hexahydroindeno[4,5h]isochromen-10-yl]acetate(also known as sonolisib)), and the structure described in WO2014/071109having the formula:

In one embodiment, a FLT3 or dual MER/FLT3 inhibitor described herein isused in combination with a modulator of the STAT5 pathway. Compoundswhich modulate the Janus Kinase 2 (JAK2)-Signal Transducer and Activatorof Transcription 5 (STAT5) pathway include but are not limited toLestaurtinib, Ruxolitinib, SB1518, CYT387, LY3009104, INC424, LY2784544,BMS-911543, NS-018, and TG101348.

In one embodiment, a FLT3 or dual MER/FLT3 inhibitor described herein isused in combination with an AKT inhibitor, including but not limited to,MK-2206, GSK690693, Perifosine, (KRX-0401), GDC-0068, Triciribine,AZD5363, Honokiol, PF-04691502, and Miltefosine.

Immunomodulatory Combination Agents.

Active compounds as described herein used in a dosage for direct effecton the diseased cell can be used in combination, with one or moreimmunotherapy agents for additive or synergistic efficacy against solidtumors. In one embodiment, a tumor associated macrophage MerTKinhibiting amount of a Mer TKI is used in combination or alternationwith the immunomodulatory agent. In another embodiment, a host tumorsurvival-signal inhibiting, antiviral or antibacterial amount of a MerTKI is used in combination or alternation with the immunomodulatoryagent.

Immunomodulators are small molecules or biologic agents that treat adisease by inducing, enhancing or suppressing the host's immune system.In the present application, one or more immunomodulators are selectedthat induce or enhance the host's immune system. Some immunomodulatorsboost the host's immune system and others help train the host's immunesystem to better attack tumor cells. Other immunomodulators targetproteins that help cancer grow.

Three general categories of immunotherapies are antibodies, cancervaccines, and non-specific immunotherapies. Antibodies are typicallyadministered as monoclonals, although that is not required. “Nakedmonoclonal antibodies” work by attaching to antigens on tumor cells.Some antibodies can act as a marker for the body's immune system todestroy the tumor cells. Others block signaling agents for tumor cells.Antibodies can generally be used to bind to any signaling or metabolicagent that directly or indirectly facilitates tumor growth. Examples arealemtuzumab (Campath) which binds to CD52 antigen, and trastuzumab(Herceptin), which binds to the HER2 protein.

In another embodiment, an antibody can be used that is conjugated toanother moiety that increases it delivery or efficacy. For example, theantibody can be connected to a cytotoxic drug or a radiolabel.Conjugated antibodies are sometimes referred to as “tagged, labeled orloaded”. Radiolabeled antibodies have small radioactive particlesattached to them. Examples are Zevalin, which is an antibody againstCD20 used to treat lymphoma. Chemolabeled antibodies are antibodies thathave cytotoxic agents attached to them. Examples are Adcetris, whichtargets CD30, and Kadcyla, which targets HER2. Ontak, while not anantibody, is similar in that it is interleukin-2 attached to a toxinfrom diphtheria.

Another category of immunotherapy that can be used in the presentinvention is a cancer vaccine. Most cancer vaccines are prepared fromtumor cells, parts of tumor cells or pure antigens. The vaccine can beused with an adjuvant to help boost the immune response. An example isProvenge, which is the first cancer vaccine approved by the US FDA. Thevaccine can for example be a dendritic cell vaccine or a vector-basedvaccine

Nonspecific tumor immunotherapies and adjuvants include compounds thatstimulate the immune system to do a better job at attacking the tumorcells. Such immunotherapies include cytokines, interleukins, interferons(a primarily but can be also β or γ). Specific agents includegranulocyte-macrophage colony-stimulating factor (GM-CSF), IL-12, IL-7,IL-21, drugs that target CTLA-4 (such as Yervoy, which is Ipilimumab)and drugs that target PD-1 or PDL-1 (such as for example, nivolumab(BMS), pembrolizumab (Merck), pidilizumab (CureTech/Teva), AMP-244(Amplimmune/GSK), BMS-936559 (BMS), and MEDI4736 (Roche/Genentech)).

Other drugs that boost the immune system are thalidomide, lenalidomide,pomalidomide, the Bacille Calmette-Gurin bacteria and Imiquimod.Additional therapeutic agents that can be used in combination with theMerTK inhibitor include bispecific antibodies, chimeric antigen receptor(CAR) T-cell therapy and tumor-infiltrating lymphocytes.

In one aspect of the present invention, a compound described herein canbe combined with at least one immunosuppressive agent. Theimmunosuppressive agent is preferably selected from the group consistingof a calcineurin inhibitor, e.g. a cyclosporin or an ascomycin, e.g.Cyclosporin A (NEORAL®), FK506 (tacrolimus), pimecrolimus, a mTORinhibitor, e.g. rapamycin or a derivative thereof, e.g. Sirolimus(RAPAMUNE®), Everolimus (Certican®), temsirolimus, zotarolimus,biolimus-7, biolimus-9, a rapalog, e.g. ridaforolimus, azathioprine,campath 1H, a S1P receptor modulator, e.g. fingolimod or an analoguethereof, an anti IL-8 antibody, mycophenolic acid or a salt thereof,e.g. sodium salt, or a prodrug thereof, e.g. Mycophenolate Mofetil(CELLCEPT®), OKT3 (ORTHOCLONE OKT3®), Prednisone, ATGAM®,THYMOGLOBULIN®, Brequinar Sodium, OKT4, T10B9.A-3A, 33B3.1,15-deoxyspergualin, tresperimus, Leflunomide ARAVA®, CTLAI-Ig,anti-CD25, anti-IL2R, Basiliximab (SIMULECT®), Daclizumab (ZENAPAX®),mizorbine, methotrexate, dexamethasone, ISAtx-247, SDZ ASM 981(pimecrolimus, Elidel®), CTLA4lg (Abatacept), belatacept, LFA3lg,etanercept (sold as Enbrel® by Immunex), adalimumab (Humira®),infliximab (Remicade®), an anti-LFA-1 antibody, natalizumab (Antegren®),Enlimomab, gavilimomab, antithymocyte immunoglobulin, siplizumab,Alefacept efalizumab, pentasa, mesalazine, asacol, codeine phosphate,benorylate, fenbufen, naprosyn, diclofenac, etodolac and indomethacin,aspirin and ibuprofen.

7. Anti-Platelet Agents

In another embodiment, a compound described herein is used in thetreatment of blot clot (thrombus) formation in a host in need thereof.In one embodiment, the host is suffering from coronary artery disease,peripheral vascular disease, or cerebrovascular disease. In oneembodiment, a compound described herein is administered to a host priorto any medical or surgical procedure in which diminished coagulationpotential is desirable. In one embodiment, an active compound disclosedherein is administered in combination with another anti-thrombotic oranti-clotting agent.

In one embodiment, a compound of Formula I, II, III, or IV, or anothercompound, as described herein, is provided for use in treating blot clot(thrombus) formation in a subject in need thereof, comprisingadministering an active compound as described herein, or apharmaceutically acceptable composition, salt, isotopic analog, orprodrug thereof. In one embodiment, the compound for use in treatingblot clot (thrombus) formation in a subject in need thereof is UNC2207A,including a pharmaceutically acceptable composition, salt, isotopicanalog or prodrug thereof.

In one embodiment, the treatment of blood clot formation is in, forexample, a subject with coronary artery disease, peripheral vasculardisease, or cerebrovascular disease, or the treatment is given prior toany medical or surgical procedure in which diminished coagulationpotential is desirable. Coronary artery disease includes, for example,any coronary dysfunction (pathological state) resulting from coronaryartherosclerosis, i.e. partial or total occlusion of coronary vessels.The term also includes a range of various acute and chronicalpathological states comprising stable and unstable angina pectoris (SAPand UAP, respectively), left ventricular dysfunction LVD, (congestive)heart failure CHF, myocardial death. Peripheral vascular diseaseincludes, for example, occlusive or functional peripheral arterialdisease (PAD). Examples of occlusive PAD include peripheral arterialocclusion, which may be acute, and Buerger's disease (thomboangiitisobliterans). Examples of functional PAD include Raynaud's disease,Raynaud's phenomenon, and acrocyanosis. Cerebrovascular diseaseincludes, for example, any abnormality of the brain resulting from apathologic process of a blood vessel. In one embodiment, thecerebrovascular disease is selected from cerebral ischemia, cerebralhemorrhage, ischemic stroke, hemorrhagic stroke, or ischemic reperfusioninjury resulting from reintroduction of blood flow following cerebralischemia or ischemic stroke. In one non-limiting embodiment, the medicalor surgical procedure is pulmonary vein ablation.

In one embodiment, the treatment of blood clot formation is in a hosthaving thrombi in blood vessels from pathologies or treatmentsincluding, for example, myocardial infarction, unstable angina, atrialfibrillation, stroke, renal damage, percutaneous translumenal coronaryangioplasty, athreosclerosis, disseminated intravascular coagulation,sepsis, endotoxemia (i.e., the presence of endotoxins in the blood),pulmonary embolism and deep vein thrombosis. In one embodiment, thecompounds described herein are administered to a host having blood clotson the surfaces of artificial organs, shunts and prostheses (forexample, artificial heart valves that are implanted into a patient), andin patients that have received an intracoronary stent. In oneembodiment, a host is administered an effective amount of a compounddescribed herein due to the formation of clots resulting from somepathological conditions (for example, genetic mutation of VWF cleavingprotease, ADAMT13), which may cause spontaneous binding of VWF toplatelets resulting in formation of microthrombi in blood vesselsleading to thrombotic thrombocytopenic purpura and othermicroangiopathy. Microangiopathy is a disease of blood vessels in whichthe walls of very small blood vessels (capillaries) become so thick andweak that they bleed, leak protein, and slow the flow of blood. In oneembodiment, the treatment is in a patient with hemolytic uremicsyndrome.

In one embodiment, an active compound disclosed herein is administeredin combination with an additional anti-platelet agent. Examples ofanti-platelet agents include, but are not limited to, aspirin, tirofiban(Aggrastat), Aggrenox, Agrylin, triflusal (Disgren), Flolan,eptifibatide (Integrilin), dipyridamole (Presantine), cilostazol(Pletal), abciximab (ReoPro), and Terutroban. In one embodiment, acompound UNC2207A is administered in combination with an additionalanti-platelet agent. In one embodiment, the Mer TKI and the additionalanti-platelet agent act synergistically. In one embodiment, the use of aMer TKI in combination with an additional anti-platelet agent providesfor increased anti-thrombotic or anti-clotting effects without anincrease in the standard of care dosage.

In one embodiment, the additional anti-platelet agent is an adenosinediphosphate (ADP) receptor inhibitor. Examples of ADP receptorinhibitors include, but are not limited to, clopidogrel (Plavix),prasugrel (Effient), ticagrelor (Brilinta), ticlopidine (Ticlid),N6-methyl-2′-deoxyadenosine-3′,5′-bisphosphate (MRS2179; P₂Y1inhibitor), and 2-methylthioadenosine 5′-monophosphate triethylammoniumsalt (2-Me-SAMP; P₂Y12 inhibitor).

In one embodiment, an active compound disclosed herein is administeredin combination with multiple anti-platelet agents. In one non-limitingembodiment, an active compound disclosed herein is administered incombination with N6-methyl-2′-deoxyadenosine-3′,5′-bisphosphate and2-methylthioadenosine 5′-monophosphate triethylammonium salt.

In one embodiment, an active compound disclosed herein is administeredin combination with an anti-coagulant. In one embodiment, theanti-coagulant is a heparin composition. In one embodiment, the heparincomposition is a low molecular weight heparin composition. Low molecularweight heparin compositions are well known to those of skill in the artand include, but are not limited to, tinzaparin, certoparin, pamaparin,nadroparin, ardeparin, enoxaparin, reviparin, dalteparin, andfraxiparin. Additional examples of anti-coagulants include, but are notlimited to, warfarin (Coumadin), Fragmin, Hep-Lock, Lovenox, andMiradon. In one embodiment, a compound UNC2207A is administered incombination with an anti-coagulant.

8. Nanoparticle Compositions or Carriers

In one aspect of the present invention, an effective amount of an activecompound as described herein is incorporated into nanoparticles, e.g.for convenience of delivery and/or extended release delivery. The use ofmaterials in nanoscale provides one the ability to modify fundamentalphysical properties such as solubility, diffusivity, blood circulationhalf-life, drug release characteristics, and immunogenicity. In the lasttwo decades, a number of nanoparticle-based therapeutic and diagnosticagents have been developed for the treatment of cancer, diabetes, pain,asthma, allergy, and infections. These nanoscale agents can provide moreeffective and/or more convenient routes of administration, lowertherapeutic toxicity, extend the product life cycle, and ultimatelyreduce health-care costs. As therapeutic delivery systems, nanoparticlesallow targeted delivery and controlled release.

In addition, nanoparticle-based drug delivery can be used to releasedrugs at a sustained rate and thus lower the frequency ofadministration, deliver drugs in a target manner to minimize systemicside effects, or deliver two or more drugs simultaneously forcombination therapy to generate a synergistic effect and suppress drugresistance. To date, a number of nanotechnology-based therapeuticproducts have been approved for clinical use. Among these products,liposomal drugs and polymer-based conjugates account for more than 80%of the products. See, Zhang, L., et al., Nanoparticles in Medicine:Therapeutic Applications and Developments, Clin. Pharm. and Ther.,83(5):761-769, 2008.

Optimal solid lipid nanoparticles (SLN) can be produced in a controlledfashion when a fraction of lipid in the crystalline alpha form can becreated and preserved. By doing this, the SLN carrier has a built intrigger mechanism as lipids transform from the alpha to beta form andconsequently control drug release. Drug release profiles can be modifiedaccording to the composition of the lipid matrix, surfactantconcentration and production parameters. See, Muller, R. H., et al.,Solid lipid nanoparticles (SLN) for controlled drug delivery—a review ofthe state of the art, Eur. H. Pharm. Biopharm., 50:161-177, 2000.Consien et al. have recently disclosed lipid nanoparticles having novelamino-lipids that form lipid nanoparticles and their use for theintracellular delivery of biologically active compounds, e.g., nucleicacids. See, U.S. Pat. No. 8,691,750 to Consien et al.

In regard to controlled release, Kanwar has recently disclosed alginateadsorbed chitosan adsorbed lactoferrin adsorbed calcium phosphatenanoparticles and the controlled release of lactoferrin from thenanoparticles. See, WO 2012/145801 to Kanwar. In addition, Armes et al.have recently disclosed polymer-templated core-shell nanoparticlesadapted to facilitate controlled release of at least one active agentinto a system in response to controlled changes in the pH of the system.See, U.S. Pat. No. 8,580,311 to Armes, S. et al. incorporated byreference herein.

Petros and DeSimone have recently reviewed strategies in the design ofnanoparticles. In addition, the authors reviewed their PRINT (particlereplication in non-wetting templates) technology for generatingmicroparticles and nanoparticles. See, Petros, R. A. and DeSimone, J.M., Strategies in the design of nanoparticles for therapeuticapplications, Nature Reviews/Drug Discovery, vol. 9:615-627, 2010.Importantly, the authors disclosed the production of nanoparticles inwhich a single parameter (shape or size) can be altered independently ofall other particle attributes. The authors concluded their paper byoutlining several particle characteristics that have emerged as beingcentral to the function of engineered nanoparticles. These parametersinclude particle size, particle shape, surface characteristics and theability to release therapeutics. Additional nanoparticle fabricationmethods can also be found in U.S. Pat. No. 8,465,775, U.S. Pat. No.8,444,899, U.S. Pat. No. 8,420,124, U.S. Pat. No. 8,263,129, U.S. Pat.Nos. 8,158,728 and 8,268,446 all hereby incorporated by reference.

Nanoparticles may be prepared using a wide variety of methods known inthe art. For example, nanoparticles can be formed by methods asnanoprecipitation, flow focusing fluidic channels, spray drying, singleand double emulsion solvent evaporation, solvent extraction, phaseseparation, milling, microemulsion procedures, microfabrication,nanofabrication, sacrificial layers, simple and complex coacervation,and other methods well known to those of ordinary skill in the art.Alternatively or additionally, aqueous and organic solvent syntheses formonodisperse semiconductor, conductive, magnetic, organic, and othernanomaterials have been described (Pellegrino et al., 2005, Small, 1:48;Murray et al., 2000, Ann. Rev. Mat. Sci., 30:545; and Trindade et al.,2001, Chem. Mat., 13:3843). Additional methods have been described inthe literature (see, e.g., Doubrow, Ed., “Microcapsules andNanoparticles in Medicine and Pharmacy,” CRC Press, Boca Raton, 1992;Mathiowitz et al., 1987, J. Control. Release, 5:13; Mathiowitz et al.,1987, Reactive Polymers, 6:275; and Mathiowitz et al., 1988, J. Appl.Polymer Sci., 35:755; U.S. Pat. Nos. 5,578,325 and 6,007,845; P.Paolicelli et al., “Surface-modified PLGA-based Nanoparticles that canEfficiently Associate and Deliver Virus-like Particles” Nanomedicine.5(6):843-853 (2010)).

In some embodiments, the compounds described herein are associated witha nanoparticle, such as a polymeric nanoparticle. Nanoparticles maycomprise natural polymers, including but not limited to chitosan,alginate, dextran, gelatin, and albumin, and synthetic polymers such as,but not limited to, poly(lactide-co-glycolide) (PLGA),(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV), poly(sebacicanhydride), poly(ε-caprolactone), polystyrene, thermoresponsive (i.e.,NIPAAm and CMCTS-g-PDEA) and pH-responsive (i.e., Eudragit L100,Eudragit S and AQOAT AS-MG) polymers.

In one embodiment, the polymeric particle is between about 0.1 nm toabout 10000 nm, between about 1 nm to about 1000 nm, between about 10 nmand 1000 nm, between about 100 nm and 800 nm, between about 400 nm and600 nm, or about 500 nm. In one embodiment, the micro-particles areabout 0.1 nm, 0.5 nm, 1.0 nm, 5.0 nm, 10 nm, 25 nm, 50 nm, 75 nm, 100nm, 150 nm, 200 nm, 250 nm, 300 nm, 400 nm, 450 nm, 500 nm, 550 nm, 600nm, 650 nm, 700 nm, 750 nm, 800 nm, 850 nm, 900 nm, 950 nm, 1000 nm,1250 nm, 1500 nm, 1750 nm, or 2000 nm. In one embodiment, the compoundsdescribed herein are covalently coupled to a polystyrene particle, PLGAparticle, PLA particle, or other nanoparticle.

In some embodiments, the nanoparticle can be solid or hollow and cancomprise one or more layers. In some embodiments, each layer has aunique composition and unique properties relative to the other layer(s).To give but one example, the nanoparticle may have a core/shellstructure, wherein the core is one layer (e.g. a polymeric core) and theshell is a second layer (e.g. a lipid bilayer or monolayer). In someembodiments, the nanoparticle may comprise a plurality of differentlayers. In some embodiments, the compounds described herein can beincorporated into or surrounded by one or more layers.

In some embodiments, the nanoparticles comprising the compoundsdescribed herein may optionally comprise one or more lipids. In someembodiments, a nanoparticle may comprise a liposome. In someembodiments, a nanoparticle may comprise a lipid bilayer. In someembodiments, a nanoparticle may comprise a lipid monolayer. In someembodiments, a nanoparticle may comprise a micelle. In some embodiments,a nanoparticle may comprise a core comprising a polymeric matrixsurrounded by a lipid layer (e.g., lipid bilayer, lipid monolayer,etc.). In some embodiments, a nanoparticle may comprise a non-polymericcore (e.g., metal particle, quantum dot, ceramic particle, boneparticle, viral particle, proteins, nucleic acids, carbohydrates, etc.)surrounded by a lipid layer (e.g., lipid bilayer, lipid monolayer,etc.).

In other embodiments, the nanoparticle may comprise metal particles,quantum dots, ceramic particles, etc. In some embodiments, anon-polymeric nanoparticle is an aggregate of non-polymeric components,such as an aggregate of metal atoms (e.g., gold atoms).

In some embodiments, nanoparticles may optionally comprise one or moreamphiphilic entities. In some embodiments, an amphiphilic entity canpromote the production of nanoparticles with increased stability,improved uniformity, or increased viscosity. In some embodiments,amphiphilic entities can be associated with the interior surface of alipid membrane (e.g., lipid bilayer, lipid monolayer, etc.). Manyamphiphilic entities known in the art are suitable for use in makingnanoparticles useful in the present invention. Such amphiphilic entitiesinclude, but are not limited to, phosphoglycerides;phosphatidylcholines; dipalmitoyl phosphatidylcholine (DPPC);dioleylphosphatidyl ethanolamine (DOPE);dioleyloxypropyltriethylammonium (DOTMA); dioleoylphosphatidylcholine;cholesterol; cholesterol ester; diacylglycerol; diacylglycerolsuccinate;diphosphatidyl glycerol (DPPG); hexanedecanol; fatty alcohols such aspolyethylene glycol (PEG); polyoxyethylene-9-lauryl ether; a surfaceactive fatty acid, such as palmitic acid or oleic acid; fatty acids;fatty acid monoglycerides; fatty acid diglycerides; fatty acid amides;sorbitan trioleate (Span®85)glycocholate; sorbitan monolaurate(Span®20); polysorbate 20 (Tween®20); polysorbate 60 (Tween®60);polysorbate 65 (Tween®65); polysorbate 80 (Tween®80); polysorbate 85(Tween®85); polyoxyethylene monostearate; surfactin; a poloxomer; asorbitan fatty acid ester such as sorbitan trioleate; lecithin;lysolecithin; phosphatidylserine; phosphatidylinositol; sphingomyelin;phosphatidylethanolamine (cephalin); cardiolipin; phosphatidic acid;cerebrosides; dicetylphosphate; dipalmitoylphosphatidyl glycerol;stearylamine; dodecylamine; hexadecyl-amine; acetyl palmitate; glycerolricinoleate; hexadecyl sterate; isopropyl myristate; tyloxapol;poly(ethylene glycol)5000-phosphatidylethanolamine; poly(ethyleneglycol)400-monostearate; phospholipids; synthetic and/or naturaldetergents having high surfactant properties; deoxycholates;cyclodextrins; chaotropic salts; ion pairing agents; and combinationsthereof. An amphiphilic entity component may be a mixture of differentamphiphilic entities. Those skilled in the art will recognize that thisis an exemplary, not comprehensive, list of substances with surfactantactivity. Any amphiphilic entity may be used in the production ofnanoparticles to be used in accordance with the present invention.

In some embodiments, a nanoparticle may optionally comprise one or morecarbohydrates. Carbohydrates may be natural or synthetic. A carbohydratemay be a derivatized natural carbohydrate. In certain embodiments, acarbohydrate comprises monosaccharide or disaccharide, including but notlimited to glucose, fructose, galactose, ribose, lactose, sucrose,maltose, trehalose, cellbiose, mannose, xylose, arabinose, glucoronicacid, galactoronic acid, mannuronic acid, glucosamine, galactosamine,and neuramic acid. In certain embodiments, a carbohydrate is apolysaccharide, including but not limited to pullulan, cellulose,microcrystalline cellulose, hydroxypropyl methylcellulose (HPMC),hydroxycellulose (HC), methylcellulose (MC), dextran, cyclodextran,glycogen, hydroxyethylstarch, carageenan, glycon, amylose, chitosan,N,O-carboxylmethylchitosan, algin and alginic acid, starch, chitin,inulin, konjac, glucommannan, pustulan, heparin, hyaluronic acid,curdlan, and xanthan. In some embodiments, the nanoparticle does notcomprise (or specifically exclude) carbohydrates, such as apolysaccharide. In certain embodiments, the carbohydrate may comprise acarbohydrate derivative such as a sugar alcohol, including but notlimited to mannitol, sorbitol, xylitol, erythritol, maltitol, andlactitol.

In some embodiments, the associated nanoparticle can comprise one ormore polymers. In some embodiments, the nanoparticle comprises one ormore polymers that are a non-methoxy-terminated, pluronic polymer. Insome embodiments, at least 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%,35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 97%, or99% (weight/weight) of the polymers that make up the nanoparticles arenon-methoxy-terminated, pluronic polymers. In some embodiments, all ofthe polymers that make up the nanoparticle are non-methoxy-terminated,pluronic polymers. In some embodiments, the nanoparticle comprises oneor more polymers that are a non-methoxy-terminated polymer. In someembodiments, at least 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%,40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 97%, or 99%(weight/weight) of the polymers that make up the nanoparticles arenon-methoxy-terminated polymers. In some embodiments, all of thepolymers that make up the nanoparticle are non-methoxy-terminatedpolymers. In some embodiments, the nanoparticle comprises one or morepolymers that do not comprise pluronic polymer. In some embodiments, atleast 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%,55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 97%, or 99% (weight/weight)of the polymers that make up the nanoparticle do not comprise pluronicpolymer. In some embodiments, all of the polymers that make up thenanoparticles do not comprise pluronic polymer. In some embodiments,such a polymer can be surrounded by a coating layer (e.g., liposome,lipid monolayer, micelle, etc.). In some embodiments, various elementsof the nanoparticle can be coupled with the polymer.

Other examples of polymers include, but are not limited topolyethylenes, polycarbonates (e.g. poly(1,3-dioxan-2one)),polyanhydrides (e.g. poly(sebacic anhydride)), polypropylfumerates,polyamides (e.g. polycaprolactam), polyacetals, polyethers, polyesters(e.g., polylactide, polyglycolide, polylactide-co-glycolide,polycaprolactone, polyhydroxyacid (e.g. poly((β3-hydroxyalkanoate))),poly(orthoesters), polycyanoacrylates, polyvinyl alcohols,polyurethanes, polyphosphazenes, polyacrylates, polymethacrylates,polyureas, polystyrenes, and polyamines, polylysine, polylysine-PEGcopolymers, and poly(ethyleneimine), poly(ethylene imine)-PEGcopolymers.

In some embodiments, nanoparticles include polymers which have beenapproved for use in humans by the U.S. Food and Drug Administration(FDA) under 21 C.F.R. §177.2600, including but not limited to polyesters(e.g., polylactic acid, poly(lactic-co-glycolic acid), polycaprolactone,polyvalerolactone, poly(1,3-dioxan-2one)); polyanhydrides (e.g.,poly(sebacic anhydride)); polyethers (e.g., polyethylene glycol);polyurethanes; polymethacrylates; polyacrylates; and polycyanoacrylates.

In some embodiments, polymers can be hydrophilic. For example, polymersmay comprise anionic groups (e.g., phosphate group, sulphate group,carboxylate group); cationic groups (e.g., quaternary amine group); orpolar groups (e.g., hydroxyl group, thiol group, amine group). In someembodiments, a nanoparticles comprising a hydrophilic polymeric matrixgenerates a hydrophilic environment within the nanoparticle. In someembodiments, polymers can be hydrophobic. In some embodiments, ananoparticles comprising a hydrophobic polymeric matrix generates ahydrophobic environment within the nanoparticle. Selection of thehydrophilicity or hydrophobicity of the polymer may have an impact onthe nature of materials that are incorporated (e.g., coupled) within thenanoparticle.

In some embodiments, polymers may be modified with one or more moietiesand/or functional groups. A variety of moieties or functional groups canbe used in accordance with the present invention. In some embodiments,polymers may be modified with polyethylene glycol (PEG), with acarbohydrate, and/or with acyclic polyacetals derived frompolysaccharides (Papisov, 2001, ACS Symposium Series, 786:301). Certainembodiments may be made using the general teachings of U.S. Pat. No.5,543,158 to Gref et al., or WO publication WO2009/051837 by Von Andrianet al.

In some embodiments, polymers may be modified with a lipid or fatty acidgroup. In some embodiments, a fatty acid group may be one or more ofbutyric, caproic, caprylic, capric, lauric, myristic, palmitic, stearic,arachidic, behenic, or lignoceric acid. In some embodiments, a fattyacid group may be one or more of palmitoleic, oleic, vaccenic, linoleic,alpha-linoleic, gamma-linoleic, arachidonic, gadoleic, arachidonic,eicosapentaenoic, docosahexaenoic, or erucic acid.

In some embodiments, polymers may be one or more acrylic polymers. Incertain embodiments, acrylic polymers include, for example, acrylic acidand methacrylic acid copolymers, methyl methacrylate copolymers,ethoxyethyl methacrylates, cyanoethyl methacrylate, aminoalkylmethacrylate copolymer, poly(acrylic acid), poly(methacrylic acid),methacrylic acid alkylamide copolymer, poly(methyl methacrylate),poly(methacrylic acid anhydride), methyl methacrylate, polymethacrylate,poly(methyl methacrylate) copolymer, polyacrylamide, aminoalkylmethacrylate copolymer, glycidyl methacrylate copolymers,polycyanoacrylates, and combinations comprising one or more of theforegoing polymers. The acrylic polymer may comprise fully-polymerizedcopolymers of acrylic and methacrylic acid esters with a low content ofquaternary ammonium groups.

In some embodiments, polymers can be cationic polymers. In general,cationic polymers are able to condense and/or protect negatively chargedstrands of nucleic acids (e.g. DNA, or derivatives thereof).Amine-containing polymers such as poly(lysine) (Zauner et al., 1998,Adv. Drug Del. Rev., 30:97; and Kabanov et al., 1995, BioconjugateChem., 6:7), poly(ethylene imine) (PEI; Boussif et al., 1995, Proc.Natl. Acad. Sci., USA, 1995, 92:7297), and poly(amidoamine) dendrimers(Kukowska-Latallo et al., 1996, Proc. Natl. Acad. Sci., USA, 93:4897;Tang et al., 1996, Bioconjugate Chem., 7:703; and Haensler et al., 1993,Bioconjugate Chem., 4:372) are positively-charged at physiological pH,form ion pairs with nucleic acids, and mediate transfection in a varietyof cell lines. In embodiments, the nanoparticles may not comprise (ormay exclude) cationic polymers.

In some embodiments, polymers can be degradable polyesters bearingcationic side chains (Putnam et al., 1999, Macromolecules, 32:3658;Barrera et al., 1993, J. Am. Chem. Soc., 115:11010; Kwon et al., 1989,Macromolecules, 22:3250; Lim et al., 1999, J. Am. Chem. Soc., 121:5633;and Zhou et al., 1990, Macromolecules, 23:3399). Examples of thesepolyesters include poly(L-lactide-co-L-lysine) (Barrera et al., 1993, J.Am. Chem. Soc., 115:11010), poly(serine ester) (Zhou et al., 1990,Macromolecules, 23:3399), poly(4-hydroxy-L-proline ester) (Putnam etal., 1999, Macromolecules, 32:3658; and Lim et al., 1999, J. Am. Chem.Soc., 121:5633), and poly(4-hydroxy-L-proline ester) (Putnam et al.,1999, Macromolecules, 32:3658; and Lim et al., 1999, J. Am. Chem. Soc.,121:5633).

The properties of these and other polymers and methods for preparingthem are well known in the art (see, for example, U.S. Pat. Nos.6,123,727; 5,804,178; 5,770,417; 5,736,372; 5,716,404; 6,095,148;5,837,752; 5,902,599; 5,696,175; 5,514,378; 5,512,600; 5,399,665;5,019,379; 5,010,167; 4,806,621; 4,638,045; and 4,946,929; Wang et al.,2001, J. Am. Chem. Soc., 123:9480; Lim et al., 2001, J. Am. Chem. Soc.,123:2460; Langer, 2000, Acc. Chem. Res., 33:94; Langer, 1999, J.Control. Release, 62:7; and Uhrich et al., 1999, Chem. Rev., 99:3181).More generally, a variety of methods for synthesizing certain suitablepolymers are described in Concise Encyclopedia of Polymer Science andPolymeric Amines and Ammonium Salts, Ed. by Goethals, Pergamon Press,1980; Principles of Polymerization by Odian, John Wiley & Sons, FourthEdition, 2004; Contemporary Polymer Chemistry by Allcock et al.,Prentice-Hall, 1981; Deming et al., 1997, Nature, 390:386; and in U.S.Pat. Nos. 6,506,577, 6,632,922, 6,686,446, and 6,818,732.

Polymers can be linear or branched polymers. In some embodiments,polymers can be dendrimers. In some embodiments, polymers can besubstantially cross-linked to one another. In some embodiments, polymerscan be substantially free of cross-links. In some embodiments, polymerscan be used without undergoing a cross-linking step. It is further to beunderstood that a nanoparticle may comprise block copolymers, graftcopolymers, blends, mixtures, and/or adducts of any of the foregoing andother polymers. Those skilled in the art will recognize that thepolymers listed herein represent an exemplary, not comprehensive, listof polymers that can be of use in accordance with the present invention.

The compounds of the present invention can be coupled to a nanoparticleby any of a number of methods. Generally, the coupling can be a resultof bonding between the compound and the nanoparticle. This bonding canresult in the compound being attached to the surface of the nanoparticleand/or contained within (encapsulated) the nanoparticle. In someembodiments, however, the compounds are encapsulated by the nanoparticleas a result of the structure of the nanoparticle rather than bonding tothe nanoparticle. In some embodiments, the nanoparticle comprises apolymer as provided herein, and the compounds described herein arecoupled to the nanoparticle. The compounds described herein may beencapsulated into nanoparticles as desirable using a variety of methodsincluding but not limited to C. Astete et al., “Synthesis andcharacterization of PLGA nanoparticles” J. Biomater. Sci. Polymer Edn,Vol. 17, No. 3, pp. 247-289 (2006); K. Avgoustakis “PegylatedPoly(Lactide) and Poly(Lactide-Co-Glycolide) Nanoparticles: Preparation,Properties and Possible Applications in Drug Delivery” Current DrugDelivery 1:321-333 (2004); C. Reis et al., “Nanoencapsulation I. Methodsfor preparation of drug-loaded polymeric nanoparticles” Nanomedicine2:8-21 (2006); P. Paolicelli et al., “Surface-modified PLGA-basedNanoparticles that can Efficiently Associate and Deliver Virus-likeParticles” Nanomedicine. 5(6):843-853 (2010). Other methods suitable forencapsulating the compounds described herein may be used, includingwithout limitation methods disclosed in U.S. Pat. No. 6,632,671 to UngerOct. 14, 2003.

In certain embodiments, nanoparticles are prepared by ananoprecipitation process or spray drying. Conditions used in preparingnanoparticles may be altered to yield particles of a desired size orproperty (e.g., hydrophobicity, hydrophilicity, external morphology,“stickiness,” shape, etc.). The method of preparing the nanoparticlesand the conditions (e.g., solvent, temperature, concentration, air flowrate, etc.) used may depend on the materials to be coupled to thenanoparticles and/or the composition of the polymer matrix. If particlesprepared by any of the above methods have a size range outside of thedesired range, particles can be sized, for example, using a sieve.

In one embodiment of the present invention, PRINT technology is used tomanufacture nanoparticles comprising a compound described herein.

In another embodiment, provided herein are liposome based nanoparticlescomprising a compound described herein. In another embodiment, aliposome based nanoparticle comprises a compound described hereinformulated for controlled-release.

In one embodiment, provided herein are polymer based nanoparticlescomprising a compound described herein. In another embodiment, providedherein are polymer based nanoparticles comprising a compound describedherein formulated for controlled-release.

In one embodiment, nanoparticles are comprised of albumin and a compounddescribed herein. In another embodiment, nanoparticles are comprised ofa polysaccharide and a compound described herein. In one embodiment,nanoparticles are comprised of a metal and a compound described herein.In another embodiment, nanoparticles are comprised of gold and acompound described herein. In another embodiment, nanoparticles arecomprised of iron oxide and a compound described herein. In oneembodiment, nanoparticles are comprised of silicon and a compounddescribed herein.

In regard to polymers used for the production of nanoparticles, severalreviews are available. See, for example, Soppimath, K. S., et al.,Biodegradable polymeric nanoparticles as drug delivery devices, J.Controlled Release, 70:1-20, 2001, Agnihotri, S. A., et al., Recentadvances on chitosan-based micro- and nanoparticle delivery, J.Controlled Release, 100(1):5-28, 2004, Ganta, S, et al., A review ofstimuli-responsive nanocarriers for drug and gene delivery, J.Controlled Release, 126(3):187-204, 2008, Danhier, F. et al., PLGA-basednanoparticles: An overview of biomedical applications, J. ControlledRelease, 161(2):505-522, 2012,

In one embodiment, nanoparticles are comprised of L-glutamic acidcopolymers and a compound described herein. In another embodiment,nanoparticles are comprised of L-alanine copolymers and a compounddescribed herein. In one embodiment, nanoparticles are comprised ofL-lysine copolymers and a compound described herein. In anotherembodiment, nanoparticles are comprised of L-tyrosine copolymers and acompound described herein. In other embodiment, nanoparticles arecomprised of poly(lactic-co-glycolic acid) and a compound describedherein. In another embodiment, nanoparticles are comprised ofmethoxy-PEG-poly(D,L-lactide) and a compound described herein. Inanother embodiment, nanoparticles are comprised of HPMA copolymer and acompound described herein. In one embodiment, nanoparticles arecomprised of polycyclodextran and a compound described herein. In oneembodiment, nanoparticles are comprised of polyglutamate and a compounddescribed herein. In another embodiment, nanoparticles are comprised ofpoly(iso-hexyl-cyanoacrylate) and a compound described herein. In oneembodiment, nanoparticles are comprised of poly-L-lysine and a compounddescribed herein. In another embodiment, nanoparticles are comprised ofPEG and a compound described herein. In one embodiment, nanoparticlesare made of combinations of polymers and a compound described herein.

In one embodiment, a compounds described herein is released from ananoparticle over a period of between about 1 and about 90 days. In oneembodiment, the compound is released over a period of about 3 to 28days. In one embodiment, the compound is released over a period of about5 to 21 days.

EXAMPLES

The present invention is explained in greater detail in the followingnon-limiting Examples.

Example 1 Syntheses of Active Compounds General Schemes

Scheme 1 illustrates a general procedure for preparing a compound of thepresent invention. Structure 1-1 can be prepared by oxiding a desired6-methylthio-1H-pyrazolo[3,4-d]pyrimidine with a desired oxiding agentaccording to methods known in the art. For example, Structure 1-1 can beprepared by treating a 6-methylthio-1H-pyrazolo[3,4-d]pyrimidine with adesired oxidizing agent, for example, 3-chloroperbenzoic acid in thepresence of an organic solvent, for example, tetrahydrofuran. It shouldbe noted that LG is a leaving group. In one embodiment, the leavinggroup is bromide. Structure 1-2 can be prepared by aminating a desiredsulfone, 1-1, with a desired amine in an organic solvent, for example,tetrahydrofuran, in the presence of a base, for example,diisopropylethylamine optionally at an elevated temperature. Structure1-3 can be prepared by treating a desired 1H-pyrazolo[3,4-d]pyrimidinewith a desired R²-LG₁ in the presence of a base and an organic solventoptionally in a microwave apparatus at an elevated temperature. Forexample, Structure 1-3 can be prepared by treating a1H-pyrazolo[3,4-d]pyrimidine with an alkyl halide, R²-LG₁, in thepresence of a base, for example, potassium carbonate, and an organicsolvent, for example, N,N-dimethylacetamide in a microwave apparatus atan elevated temperature, for example, at about 150° C. In oneembodiment, LG₁ is a halide. In one embodiment, LG₁ is chloride. Acompound of Formula I can be prepared by treating Structure 1-3, havinga leaving group LG, with a borane reagent, an organometallic reagent, abase, a solvent(s) in a microwave apparatus optionally at an elevatedtemperature. For example, a compound of Formula I can be prepared bytreating a compound with a leaving group, for example, a halide, with aborane reagent, for example,1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1,4-diazepane,an organometallic reagent, for example,tetrakis(triphenylphosphine)palladium(0), a base, for example, potassiumcarbonate in a solvent(s) optionally at an elevated temperature. In oneembodiment, the solvents are dioxane and water. In one embodiment, thereaction is carried out in a microwave apparatus at about 150° C. Itwill also be appreciated by those skilled in the art that other leavinggroups can be used at the three and six-positions of1H-pyrazolo[3,4-d]pyrimidines to generate compounds of Formula I. Thischemistry is illustrated in Scheme 1.

Scheme 2 illustrates a general procedure for preparing a compound of thepresent invention. Structure 2-1 can be prepared by oxiding a desired6-methylthio-1H-pyrazolo[3,4-d]pyrimidine with a desired oxiding agentaccording to methods known in the art. For example, Structure 2-1 can beprepared by treating a 6-methylthio-1H-pyrazolo[3,4-d]pyrimidine with adesired oxidizing agent, for example, 3-chloroperbenzoic acid in thepresence of an organic solvent, for example, tetrahydrofuran. It shouldbe noted that LG is a leaving group. In one embodiment, the leavinggroup is bromide. Structure 2-2 can be prepared by aminating a desiredsulfone, 2-1, with a desired amine in an organic solvent, for example,tetrahydrofuran, in the presence of a base, for example,diisopropylethylamine optionally at an elevated temperature. Structure2-3 can be prepared by treating a desired 1H-pyrazolo[3,4-d]pyrimidinewith a desired R¹²-LG₁ in the presence of a base and an organic solventoptionally in a microwave apparatus at an elevated temperature. Forexample, Structure 2-3 can be prepared by treating a1H-pyrazolo[3,4-d]pyrimidine with an alkyl halide, R¹²-LG₁, in thepresence of a base, for example, potassium carbonate, and an organicsolvent, for example, N,N-dimethylacetamide in a microwave apparatus atan elevated temperature, for example, at about 150° C. In oneembodiment, LG₁ is a halide. In one embodiment, LG₁ is chloride. Acompound of Formula II can be prepared by treating Structure 2-3, havinga leaving group LG, with a borane reagent, an organometallic reagent, abase, and a solvent(s) in a microwave apparatus optionally at anelevated temperature. For example, a compound of Formula II can beprepared by treating a compound with a leaving group, for example, ahalide, with a borane reagent, for example,1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1,4-diazepane,an organometallic reagent, for example,tetrakis(triphenylphosphine)palladium(0), a base, for example, potassiumcarbonate in a solvent(s) optionally at an elevated temperature. In oneembodiment, the solvents are dioxane and water. In one embodiment, thereaction is carried out in a microwave apparatus at about 150° C. Itwill also be appreciated by those skilled in the art that other leavinggroups can be used at the three and six-positions of1H-pyrazolo[3,4-d]pyrimidines to generate compounds of Formula II. Thischemistry is illustrated in Scheme 2.

Compounds of Formula I or Formula II can be metabolized to generatepyrazolopyrimidine compounds. In one embodiment, a compound of Formula Ior Formula II can be dealkylated. For example, a compound of Formula Ican be dealkylated at R³ to generate R³=NH₂. In one embodiment, acompound of Formula II can be dealkylated. For example, a compound ofFormula II can be dealkylated at R¹³ to generate R¹³=NH₂. In oneembodiment, a compound of Formula I comprising a methylated amine can bedemethylated. In another embodiment, a compound of Formula II comprisinga methylated amine can be demethylated. In one embodiment, a compound ofFormula I or Formula II can be oxidized. For example, a compound ofFormula I or Formula II comprising a piperazine group can be oxidized togenerate a piperazine N-oxide. In another embodiment, a compound ofFormula I or Formula II comprising a piperazine group can be oxidizedtwice to generate a piperazine bis-N-oxide. In another embodiment, acompound of Formula I or Formula II can be oxidized to generate apyrazolopyrimidine N-oxide. The metabolic pathways described above areillustrated below, in Scheme 3, with the example compound UNC2207.

Example 2 Synthesis of Compounds UNC 2207A and 2208A

The synthesis of compounds UNC2207A and 2208A is given below. Bothcompounds have a MerTK IC₅₀ below 10 nM.

General Procedure F:

3-Bromo-N-butyl-1H-pyrazolo[3,4-d]pyrimidin-6-amine

To a mixture of 3-bromo-6-(methylthio)-1H-pyrazolo[3,4-d]pyrimidine(1.95 g, 8.0 mmol) in THF (20.0 mL) was added meta-chloroperoxybenzoicacid (2.68 g, 77%, 11.9 mmol) at room temperature. The white mixture wasstirred for 2 h and transferred into a THF (25.0 mL) solution ofn-butylamine (4.0 mL, 40 mmol) at 0° C. The resulting solution wasallowed to warm to room temperature and stirred for 2.0 h. After removalof the solvent under reduced pressure, MeOH was added and the mixturewas filtered. The white solid was washed with MeOH (3×) and dried toprovide 3-bromo-N-butyl-1H-pyrazolo[3,4-d]pyrimidin-6-amine (1.80 g,84%) as a white solid. ¹H NMR (400 MHz, dmso-d⁶) δ 8.59 (s, 1H), 7.63(s, 1H), 3.37-3.11 (m, 3H), 1.54-1.41 (m, 2H), 1.29 (dq, J=14.4, 7.3 Hz,2H), 0.84 (t, J=7.3 Hz, 3H); ¹³C NMR (101 MHz, DMSO-d⁶) δ 162.0, 157.4,153.1, 120.5, 107.1, 41.0, 31.0, 20.1, 14.2; MS m/z 270.10 [M+H]⁺.

Trans-4-(3-bromo-6-(butylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexanol

To a solution of 3-bromo-N-butyl-1H-pyrazolo[3,4-d]pyrimidin-6-amine(500 mg, 1.85 mmol) and trans-4-hydroxy-cyclohexyl chloride (722 mg,5.56 mmol) in DMF (50 mL) was added K₂CO₃ (1.02 g, 7.4 mmol). Themixture was heated at 150° C. for 12 h. After the reaction was cooled toroom temperature, the reaction was quenched with H₂O. The reactionmixture was partitioned between H₂O and EtOAc. The aqueous phase wasextracted with EtOAc (3×). The combined organic phase were dried(Na₂SO₄) and concentrated. The residue was purified by ISCO to provide(trans)-4-(3-bromo-6-(butylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexanolas a white solid (558.6 mg) in 82% yield. NMR (400 MHz, CD₃OD) δ 8.49(s, 1H), 4.59-4.41 (m, 1H), 3.69-3.56 (m, 1H), 3.42 (t, J=7.1 Hz, 2H),2.13-2.00 (m, 4H), 1.98-1.89 (m, 2H), 1.66-1.56 (m, 2H), 1.52-1.36 (m,4H), 0.96 (t, J=7.4 Hz, 3H); ¹³C NMR (101 MHz, dmso-d⁶) δ 161.6, 155.0,153.4, 119.1, 110.3, 107.7, 68.3, 55.5, 34.6, 30.9, 29.8, 20.0, 14.1; MSm/z 369.10 [M+H]⁺.

Trans-4-(6-(butylamino)-3-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexanol(UNC2207A)

A mixture of(trans)-4-(3-bromo-6-(butylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexanol(250 mg, 0.68 mmol),1-methyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]piperazine(322 mg, 1.02 mmol), potassium carbonate (188 g, 1.36 mmol) andtetrakis(triphenylphosphine)palladium (39.3 mg, 0.034 mmol) in a mixtureof dioxane (2.5 mL) and water (0.50 mL) was stirred at room temperaturefor 5 min, then was heat under microwave irradiation at 150° C. for 20min. The reaction was diluted with EtOAc and washed with water. Theaqueous layer was extracted with EtOAc (3×). The combined organic layerswere dried (Na₂SO₄), concentrated, the residue was purified by ISCOfollowed by HPLC to give(trans)-4-(6-(butylamino)-3-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexanol(UNC2207A, TFA salt) (256 mg, 56%) as a yellow solid. ¹H NMR (400 MHz,CD₃OD) δ 9.06 (s, 1H), 7.98-7.90 (m, 2H), 7.53 (d, J=8.3 Hz, 2H),4.71-4.60 (m, 1H), 3.82 (s, 2H), 3.75-3.67 (m, 1H), 3.52 (t, J=7.1 Hz,2H), 3.40-3.30 (m, 4H), 2.99-2.89 (m, 2H), 2.88 (s, 3H), 2.87-2.70 (m,2H), 2.26-2.10 (m, 4H), 2.09-1.99 (m, 2H), 1.73-1.64 (m, 2H), 1.58-1.43(m, 4H), 1.01 (t, J=7.4 Hz, 3H); MS m/z 478.35 [M+H]⁺.

Trans-4-(6-(butylamino)-3-(4-(morpholinomethyl)phenyl)-1H-pyrazolo[3,4-a]pyrimidin-1-yl)cyclohexanol(UNC2208A)

A mixture of(trans)-4-(3-bromo-6-(butylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexanol(250 mg, 0.68 mmol), 4-(4-morpholinomethyl)phenylboronic acid pinacolester (309 mg, 1.02 mmol), potassium carbonate (188 g, 1.36 mmol),tetrakis(triphenylphosphine) palladium (39.3 mg, 0.034 mmol) in amixture of dioxane (2.5 mL) and water (0.50 mL) was stirred at roomtemperature for 5 min, then was heat under microwave irradiation at 150°C. for 20 min. The reaction was diluted with EtOAc and washed withwater. The aqueous layer was extracted with EtOAc (3×). The combinedorganic layers were dried (Na₂SO₄), concentrated, the residue waspurified by ISCO followed by HPLC to give(trans)-4-(6-(Butylamino)-3-(4-(morpholinomethyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexanol(UNC2208A, TFA salt) (255 mg, 57%) as a yellow solid. ¹H NMR (400 MHz,cd3od) δ 9.12-9.06 (m, 1H), 8.12-8.02 (m, 2H), 7.72-7.63 (m, 2H),4.71-4.60 (m, 1H), 4.43 (s, 2H), 4.16-3.93 (m, 2H), 3.87-3.64 (m, 3H),3.52 (t, J=7.1 Hz, 2H), 3.42-3.36 (m, 1H), 3.33-3.29 (m, 2H), 3.27-3.20(m, 1H), 2.27-2.09 (m, 4H), 2.09-1.98 (m, 2H), 1.73-1.64 (m, 2H),1.61-1.39 (m, 4H), 1.01 (t, J=7.4 Hz, 3H); MS m/z 465.35 [M+H]⁺.

Trans-4-(6-((2-cyclopropylethyl)amino)-3-(4-(morpholinomethyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexanol(UNC2527A)

A mixture oftrans-4-(3-bromo-6-((2-cyclopropylethyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexanol(55 mg, 0.14 mmol), 4-(4-morpholinomethyl)phenylboronic acid pinacolester HCl salt (71 mg, 0.21 mmol), potassium carbonate (40 mg, 0.28mmol), tetrakis(triphenylphosphine) palladium (16 mg, 0.014 mmol) in amixture of dioxane (2.0 mL) and water (0.50 mL) was stirred at roomtemperature for 5 min, then was heat under microwave irradiation at 150°C. for 15 min. The reaction was diluted with EtOAc and washed withwater. The aqueous layer was extracted with EtOAc (3×). The combinedorganic layers were dried (Na₂SO₄), concentrated, the residue wasfiltered through Celite cup and purified by HPLC to givetrans-4-(6-((2-cyclopropylethyl)amino)-3-(4-(morpholinomethyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexanol(UNC2527A, TFA salt) (48 mg, 72%) as a yellow solid. ¹H NMR (400 MHz,CD₃OD) δ 9.22 (s, 1H), 8.14-8.04 (d, J=8.4 Hz, 2H), 7.71 (d, J=8.4 Hz,2H), 4.68 (tt, J=11.5, 3.9 Hz, 1H), 4.45 (s, 2H), 4.04 (bs, 2H), 3.74(m, 3H), 3.66 (dd, J=14.9, 7.9 Hz, 2H), 3.40 (bs, 2H), 3.27 (bs, 2H),2.34-2.04 (m, 6H), 1.68-1.48 (m, 4H), 0.89-0.75 (m, 1H), 0.59-0.44 (m,2H), 0.21-0.12 (m, 2H); ¹³C NMR (100 MHz, CD₃OD) δ 156.5, 155.3, 148.3,146.9, 134.0, 133.3, 131.2, 128.8, 107.3, 70.1, 64.9, 61.4, 57.1, 52.9,42.9, 34.9, 34.8, 30.5, 9.5, 4.8; MS m/z 477.3 [M+H]⁺.

Trans-4-(6-((2-cyclopropylethyl)amino)-3-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexanol(UNC2528A)

A mixture oftrans-4-(3-bromo-6-((2-cyclopropylethyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexanol(55 mg, 0.14 mmol),1-methyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]piperazine(66 mg, 0.21 mmol), potassium carbonate (40 mg, 0.28 mmol),tetrakis(triphenylphosphine) palladium (16 mg, 0.014 mmol) in a mixtureof dioxane (2.0 mL) and water (0.50 mL) was stirred at room temperaturefor 5 min, then was heat under microwave irradiation at 150° C. for 15min. The reaction was diluted with EtOAc and washed with water. Theaqueous layer was extracted with EtOAc (3×). The combined organic layerswere dried (Na₂SO₄), concentrated, the residue was filtered through aplug of Celite and purified by HPLC to givetrans-4-(6-((2-cyclopropylethyl)amino)-3-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexanol(UNC2528A, TFA salt) (52 mg, 76%) as a yellow solid. ¹H NMR (400 MHz,CD₃OD) δ 9.21 (s, 1H), 8.04 (d, J=8.3 Hz, 2H), 7.67 (d, J=8.4 Hz, 2H),4.73-4.62 (m, 1H), 4.29 (s, 2H), 3.72 (m, 1H), 3.68-3.62 (m, 2H), 3.57(bs, 4H), 3.42 (bs, 4H), 2.96 (s, 3H), 2.26-2.02 (m, 6H), 1.66-1.47 (m,4H), 0.88-0.76 (m, 1H), 0.55-0.47 (m, 2H), 0.19-0.11 (m, 2H); ¹³C NMR(100 MHz, CD₃OD) δ 156.4, 154.8, 147.8, 147.4, 134.9, 132.9, 132.3,128.6, 107.3, 70.0, 61.3, 57.1, 52.8, 50.0, 43.4, 42.9, 34.9, 34.8,30.5, 9.4, 4.8; MS m/z 490.3 [M+H]⁺.

Table 1 describes compounds prepared following procedures described inExamples 1 and 2 (General Procedure A), using appropriate reagents.(Note: MerTK IC50: ++++ means <10 nM concentration required to inhibitthe MerTK enzyme by 50%.)

TABLE 1 Physical Data MS m/z (M + 1) Compound_ Mer or/and ¹H NMR (400Structure ID IC₅₀ MHz) 1

UNC2527A ++++ ¹H NMR (400 MHz, CD₃OD) δ 9.22 (s, 1H), 8.14-8.04 (d, J =8.4 Hz, 2H), 7.71 (d, J = 8.4 Hz, 2H), 4.68 (tt, J = 11.5, 3.9 Hz, 1H),4.45 (s, 2H), 4.04 (bs, 2H), 3.74 (m, 3H), 3.66 (dd, J = 14.9, 7.9 Hz,2H), 3.40 (bs, 2H), 3.27 (bs, 2H), 2.34- 2.04 (m, 6H), 1.68-1.48 (m,4H), 0.89-0.75 (m, 1H), 0.59-0.44 (m, 2H), 0.21-0.12 (m, 2H); ¹³C NMR(100 MHz, CD₃OD) δ 156.5, 155.3, 148.3, 146.9, 134.0, 133.3, 131.2,128.8, 107.3, 70.1, 64.9, 61.4, 57.1, 52.9, 42.9, 34.9, 34.8, 30.5, 9.5,4.8; ¹³C NMR (100 MHz, CD₃OD) δ 156.5, 155.3, 148.3, 146.9, 134.0,133.3, 131.2, 128.8, 107.3, 70.1, 64.9, 61.4, 57.1, 52.9, 42.9, 34.9,34.8, 30.5, 9.5, 4.8; MS m/z 477.3 [M + H]⁺. 2

UNC2528A ++++ ¹H NMR (400 MHz, CD₃OD). δ 9.21 (s, 1H), 8.04 (d, J = 8.3Hz, 2H), 7.67 (d, J = 8.4 Hz, 2H), 4.73-4.62 (m, 1H), 4.29 (s, 2H), 3.72(m, 1H), 3.68-3.62 (m, 2H), 3.57 (bs, 4H), 3.42 (bs, 4H), 2.96 (s, 3H),2.26-2.02 (m, 6H), 1.66-1.47 (m, 4H), 0.88-0.76 (m, 1H), 0.55-0.47 (m,2H), 0.19- 0.11 (m, 2H); ¹³C NMR (100 MHz, CD₃OD) δ 156.4, 154.8, 147.8,147.4, 134.9, 132.9, 132.3, 128.6, 107.3, 70.0, 61.3, 57.1, 52.8, 50.0,43.4, 42.9, 34.9, 34.8, 30.5, 9.4, 4.8; ¹³C NMR (100 MHz, CD₃OD) δ156.4, 154.8, 147.8, 147.4, 134.9, 132.9, 132.3, 128.6, 107.3, 70.0,61.3, 57.1, 52.8, 50.0, 43.4, 42.9, 34.9, 34.8, 30.5, 9.4, 4.8; MS m/z490.3 (M + 1). 3

UNC3568A ++++ ¹H NMR (400 MHz, cd₃od) δ 9.09 (s, 1H), 8.07 (d, J = 8.3Hz, 2H), 7.72 (d, J = 8.3 Hz, 2H), 4.71- 4.59 (m, 1H), 3.94-3.77 (m,4H), 3.74-3.64 (m, 1H), 3.50 (t, J = 7.1 Hz, 2H), 3.39-3.30 (m, 2H),2.26-2.08 (m, 4H), 2.08- 1.99 (m, 2H), 1.73-1.59 (m, 4H), 1.58-1.42 (m,4H), 1.38-1.28 (m, 2H), 0.99 (t, J = 7.4 Hz, 3H); MS m/z 491.3 (M + 1).4

UNC3569A ++++ ¹H NMR (400 MHz, cd₃od) δ 9.10 (s, 1H), 8.07 (d, J = 8.3Hz, 2H), 7.73 (d, J = 8.3 Hz, 2H), 4.70- 4.60 (m, 1H), 3.94-3.78 (m,4H), 3.75-3.66 (m, 1H), 3.62-3.54 (m, 2H), 3.39-3.31 (m, 2H), 2.25- 2.09(m, 4H), 2.08-1.98 (m, 2H), 1.67-1.46 (m, 6H), 1.38-1.28 (m, 2H), 0.79(dq, J = 7.8, 5.1 Hz, 1H), 0.52-0.43 (m, 2H), 0.16-0.09 (m, 2H); MS m/z503.3 (M + 1). 5

UNC3574A ++++ ¹H NMR (400 MHz, cd₃od) δ 9.13 (s, 1H), 7.98-7.89 (m, 2H),7.53- 7.45 (m, 2H), 4.71-4.57 (m, 1H), 3.75-3.63 (m, 1H), 3.54 (t, J =7.1 Hz, 2H), 3.48-3.30 (m, 2H), 3.27-3.12 (m, 2H), 3.10- 2.91 (m, 2H),2.79 (s, 3H), 2.60-2.33 (m, 2H), 2.26-1.98 (m, 6H), 1.75- 1.63 (m, 2H),1.57-1.41 (m, 4H), 1.06 (q, J = 4.1 Hz, 2H), 1.00 (t, J = 7.4 Hz, 3H),0.92 (q, J = 4.4 Hz, 2H); MS m/z 504.4 (M + 1). 6

UNC3575A ++++ ¹H NMR (400 MHz, cd₃od) δ 9.13 (d, J = 1.6 Hz, 1H),7.98-7.87 (m, 2H), 7.54-7.44 (m, 2H), 4.69-4.59 (m, 1H), 3.75- 3.66 (m,1H), 3.62 (t, J = 7.2 Hz, 2H), 3.39 (dd, J = 30.4, 18.9 Hz, 2H), 3.26-2.90 (m, 4H), 2.79 (s, 3H), 2.55-2.36 (m, 2H), 2.34-2.26 (m, 1H), 2.22-2.10 (m, 3H), 2.10-1.97 (m, 2H), 1.63-1.56 (m, 2H), 1.58-1.45 (m, 2H),1.06 (q, J = 4.1 Hz, 2H), 0.92 (q, J = 4.4 Hz, 2H), 0.85-0.75 (m, 1H),0.54- 0.44 (m, 2H), 0.18-0.08 (m, 2H); MS m/z 516.4 (M + 1).

General Structure:

Example 31-((4-Aminocyclohexyl)methyl)-N-methyl-3-p-tolyl-1H-pyrazolo[3,4-d]pyrimidin-6-amineGeneral Procedure A:

3-Bromo-6-(methylthio)-1H-pyrazolo[3,4-d]pyrimidine

To a suspension of 6-(methylthio)-1H-pyrazolo[3,4-d]pyrimidin-3(2H)-one(0.50 g, 2.7 mmol) in CH₃CN (15 mL) was added a CH₃CN solution ofP(O)Br₃ (1.57 g, 5.5 mmol) in a pressure vessel. The mixture wassonicated for 30 min before being heated to 100° C. for 16 h(overnight). After it was cooled to 0° C., H₂O and aqueous ammoniumhydroxide were added to basify the mixture. The mixture was stirred at0° C. for 1 h. The aqueous layer was extracted with EtOAc (10×). Thecombined EtOAc layer was dried (Na₂SO₄), and concentrated to give3-bromo-6-(methylthio)-1H-pyrazolo[3,4-d]pyrimidine (0.51 g, 77%) as abrown solid. ¹H NMR (400 MHz, DMSO-d6) δ: 9.00 (s, 1H), 5.57 (s, 3H); MSm/z 245.00 [M+H]⁺.

tert-Butyl4-((3-bromo-6-(methylthio)-1H-pyrazolo[3,4-d]pyrimidin-1-methyl)cyclohexylcarbamate

A 10 mL microwave tube was charged with3-bromo-6-(methylthio)-1H-pyrazolo[3,4-d]pyrimidine (0.3 g, 1.22 mmol),K₂CO₃ (0.51 g, 3.66 mmol), and DMSO (2 mL). The mixture was stirred for20 min before 4-(bromomethyl)cyclohexylcarbamate (0.45 g, 1.53 mmol) andTHF (4 mL) was added. The resulting mixture was heated at 150° C. for 10minutes in microwave. The reaction mixture was poured into water andextracted with Et₂O (3×). The combined ether layer was dried (Na₂SO₄)and concentrated. The crude mixture was purified by Isco to providetert-butyl4-((3-bromo-6-(methylthio)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)cyclohexylcarbamate(0.46 g, 83%) as a white solid. MS m/z 478.10 [M+Na]⁺.

tert-Butyl4-((3-bromo-6-(methylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)cyclohexylcarbamate

To a solution of tert-butyl4-((3-bromo-6-(methylthio)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)cyclohexylcarbamate(0.91 g, 2.0 mmol) in CH₂Cl₂ (30 mL) was added meta-Chloroperoxybenzoicacid (1.34 g, 77%, 6 mmol) at room temperature. The color of thesolution changed to light purple from colorless. After 2 h, the reactionwas diluted with EtOAc. The organic solution was then washed with 1 NNaOH (3×), dried (NaSO₄), and concentrated. The resulting residue wasdissolved in THF (10 mL) before a 2.0 M methylamine solution in THF (10mL, 20 mmol) was added at room temperature. The resulting solution washeated at 60° C. for 2 h. After removal of the solvent, it was purifiedby Isco to provide tert-butyl4-((3-bromo-6-(methylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)cyclohexylcarbamate(0.75 g, 85%) as a white solid. MS m/z 439.2 [M+H]⁺.

tert-Butyl4-((6-(methylamino)-3-p-tolyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)cyclohexylcarbamate

A 30 mL microwave tube was charged with tert-butyl4-((3-bromo-6-(methylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)cyclohexylcarbamate(0.070 g, 0.16 mmol), p-tolylboronic acid (0.065 g, 0.48 mmol),potassium phosphonate (0.10 g, 0.48 mmol),tetrakis(triphenylphosphine)palladium (0.018 g, 0.016 mmol), dioxane (2mL) and water (0.5 mL) After stirring for 5 min, the reaction was heatat 150° C. for 10 min in microwave. The reaction was diluted with EtOAcand washed with water. The aqueous layer was extracted with EtOAc (3×).The combined organic layers were dried (Na₂SO₄), concentrated, andpurified by Isco to provide tert-butyl4-((6-(methylamino)-3-p-tolyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)cyclohexylcarbamate(0.064 g, 89%) as a white solid.

1-((4-Aminocyclohexyl)methyl)-N-methyl-3-p-tolyl-1H-pyrazolo[3,4-c]pyrimidin-6-amine

To a solution of tert-butyl4-((6-(methylamino)-3-p-tolyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)cyclohexylcarbamate(0.064 g, 0.14 mmol) in CH₂Cl₂ (2 mL) was added trifluoroacetic acid(0.6 mL) at ambient temperature. After stirring for 2 h, the solvent wasevaporated. The residue was purified by preparative HPLC to provide1-((4-aminocyclohexyl)methyl)-N-methyl-3-p-tolyl-1H-pyrazolo[3,4-d]pyrimidin-6-amine(UNC00000478A) as a yellow solid (TFA salt) (0.063 g, 95%). MS m/z 351.3[M+H]⁺.

Table 2 describes compounds prepared following procedures described inExample 3 (General Procedure A), using appropriate reagents. (Note:MerTK IC50: ++++ means <10 nM; +++ means between 10-100 nM, ++ meansbetween 100 nM-1 μM; + means between 1-30 μM; − means inactive.)

TABLE 2 Physical Data dr MS m/z (M + 1) or/and Compound_ cis: Mer ¹H NMR(400 MHz, Structure ID trans IC₅₀ CD₃OD) 1

UNC00000353A 1.7:1   +++ MS m/z 355.20 (M + 1). 2

UNC00000354A 1.3:1   +++ MS m/z 355.20 (M + 1). 3

UNC00000391A 1.5:1   ++ MS m/z 355.20 (M + 1). 4

UNC00000488A 2:1 +++ MS m/z 371.20 (M + 1). 5

UNC00000355A 1.7:1   ++ MS m/z 367.20 (M + 1). 6

UNC00000356A 1.8:1   +++ MS m/z 367.20 (M + 1). 7

UNC00000392A 1.8:1   + MS m/z 367.20 (M + 1). 8

UNC00000486A 2:1 ++ MS m/z 405.20 (M + 1). 9

UNC00000481A 1:1 +++ MS m/z 395.20 (M + 1). 10

UNC00000482A 2:1 ++ MS m/z 362.20 (M + 1). 11

UNC00000492A 2:1 +++ MS m/z 415.20 (M + 1). 12

UNC00000487A 2:1 +++ MS m/z 443.30 (M + 1). 13

UNC00000394A 2.1:1   ++ MS m/z 381.20 (M + 1). 14

UNC00000397A 1.9:1   ++ MS m/z 387.30 (M + 1). 15

UNC00000484A 2:1 ++ MS m/z 376.30 (M + 1). 16

UNC00000485A 2:1 ++ MS m/z 427.20 (M + 1). 17

UNC00000393A 1.7:1   +++ MS m/z 413.30 (M + 1). 18

UNC00000483A 2:1 +++ MS m/z 457.30 (M + 1). 19

UNC00000395A 2:1 ++ MS m/z 327.20 (M + 1). 20

UNC00000396A 1.6:1   ++ MS m/z 327.20 (M + 1). 21

UNC00000398A 1.7:1   ++ MS m/z 343.20 (M + 1). 22

UNC00000399A 0.9:1   +++ MS m/z 343.20 (M + 1). 23

UNC00000491A 2:1 ++ MS m/z 393.20 (M + 1). 24

UNC00000480A 2.5:1   ++ MS m/z 327.20 (M + 1). 25

UNC00000400A 1:0 + MS m/z 339.20 (M + 1). 26

UNC00000410A 1:0 + MS m/z 354.30 (M + 1). 27

UNC00000411A 0:1 ++ MS m/z 354.30 (M + 1). 28

UNC00000490A 2:1 ++ MS m/z 338.20 (M + 1). 29

UNC00000479A 2:1 ++ MS m/z 356.30 (M + 1). 30

UNC00000489A 2:1 +++ MS m/z 422.30 (M + 1). 31

UNC00000563A 1.7:1   +++ MS m/z 421.30 (M + 1). 32

UNC00000564A 1.6:1   +++ MS m/z 422.30 (M + 1). 33

UNC00000569A 0:1 ++++ ¹H NMR (400 MHz, CD₃OD) δ 9.08 (s, 1H), 8.02-7.92(m, 2H), 7.33- 7.20 (m, 2H), 4.22 (m, 2H), 3.51 (t, J = 7.1 Hz, 2H),3.13-3.00 (m, 1H), 2.15-1.98 (m, 3H), 1.85 (d, J = 12.2 Hz, 2H), 1.74-1.62 (m, 2H), 1.55-1.20 (m, 6H), 1.00 (t, J = 7.4 Hz, 3H); MS m/z 397.30(M + 1). 34

UNC00000570A 0:1 ++++ ¹H NMR (400 MHz, CD₃OD) δ 9.16 (s, 1H), 8.76 (d, J= 2.3 Hz, 1H), 8.23 (dd, J = 2.4, 9.0 Hz, 1H), 7.11 (d, J = 9.0 Hz, 1H),4.02-3.90 (m, 4H), 3.54 (t, J = 7.1 Hz, 2H), 3.40-3.34 (m, 4H), 3.13-3.02 (m, 1H), 2.15-2.01 (m, 3H), 1.87 (d, J = 11.7 Hz, 2H), 1.75-1.65(m, 2H), 1.55-1.20 (m, 6H), 1.01 (t, J = 7.4 Hz, 3H); MS m/z 464.30 (M +1). 35

UNC583A 0:1 ++++ ¹H NMR (400 MHz, CD₃OD) δ 9.14 (s, 1H), 7.90 (d, J =8.7 Hz, 2H), 7.17 (d, J = 8.8 Hz, 2H), 4.22 (d, J = 6.8 Hz, 2H),3.60-3.50 (m, 6H), 3.44- 3.37 (m, 4H), 3.15-3.07 (m, 1H), 2.14-2.01 (m,3H), 1.87 (d, J = 11.9 Hz, 2H), 1.75-1.62 (m, 2H), 1.54-1.20 (m, 6H),1.01 (t, J = 7.4 Hz, 3H); MS m/z 463.35 (M + 1). 36

UNC582A 0:1 ++++ ¹H NMR (400 MHz, CD₃OD) δ 9.12-9.07 (m, 1H), 7.85 (d, J= 8.8 Hz, 2H), 7.10 (d, J = 8.8 Hz, 2H), 4.21 (d, J = 6.8 Hz, 2H),3.90-3.81 (m, 4H), 3.53 (t, J = 6.5 Hz, 2H), 3.29-3.23 (m, 4H), 3.12-3.02 (m, 1H), 2.06 (d, J = 11.5 Hz, 3H), 1.86 (d, J = 12.1 Hz, 2H),1.75-1.64 (m, 2H), 1.54-1.21 (m, 6H), 1.01 (t, J = 7.3 Hz, 3H); MS m/z464.40 (M + 1). 37

UNC00000548A 2:1 + MS m/z 351.30 (M + 1). 38

UNC580A 0:1 ++++ ¹H NMR (400 MHz, CD₃OD) δ 9.06 (s, 1H), 8.01-7.93 (m,2H), 7.31- 7.20 (m, 6H), 7.20-7.13 (m, 1H), 4.17 (d, J = 6.8 Hz, 2H),3.51 (t, J = 7.1 Hz, 2H), 3.09-2.95 (m, 1H), 2.75 (t, J = 7.5 Hz, 2H),2.09-1.96 (m, 5H), 1.81 (d, J = 12.4 Hz, 2H), 1.44-1.15 (m, 4H); MS m/z459.30 (M + 1). 39

UNC586A 0:1 ++++ ¹H NMR (400 MHz, CD₃OD) δ 9.14 (s, 1H), 8.76 (d, J =2.2 Hz, 1H), 8.22 (dd, J = 9.0, 2.4 Hz, 1H), 7.31-7.21 (m, 4H),7.21-7.15 (m, 1H),7.10 (d, J = 9.0 Hz, 1H), 4.18 (d, J = 6.7 Hz, 2H),3.99- 3.91 (m, 4H), 3.55 (t, J = 7.1 Hz, 2H), 3.41-3.33 (m, 4H),3.09-2.98 (m, 1H), 2.76 (t, J = 7.5 Hz, 2H), 2.11-1.97 (m, 5H), 1.82 (d,J = 11.7 Hz, 2H), 1.38 (dd, J = 23.7, 11.0 Hz, 2H), 1.23 (dd, J = 25.0,11.1 Hz, 2H); MS m/z 526.40 (M + 1). 40

UNC607A 0:1 ++++ ¹H NMR (400 MHz, CD₃OD) δ 9.08 (s, 1H), 7.89 (d, J =8.9 Hz, 2H), 7.31-7.21 (m, 4H), 7.21- 7.14 (m, 3H), 4.17 (d, J = 6.8 Hz,2H), 3.59-3.50 (m, 6H), 3.44-3.37 (m, 4H), 3.09-2.97 (m, 1H), 2.76 (t, J= 7.5 Hz, 2H), 2.11-1.95 (m, 5H), 1.82 (d, J = 11.9 Hz, 2H), 1.37 (dd, J= 23.8, 11.5 Hz, 2H), 1.23 (dd, J = 24.7, 11.3 Hz, 2H); MS m/z 525.45(M + 1). 41

UNC608A 0:1 ++++ ¹H NMR (400 MHz, CD₃OD) δ 9.04 (s, 1H), 7.84 (d, J =8.9 Hz, 2H), 7.33-7.21 (m, 4H), 7.21- 7.15 (m, 1H), 7.10 (d, J = 8.9 Hz,2H), 4.16 (d, J = 6.8 Hz, 2H), 3.89-3.82 (m, 4H), 3.52 (t, J = 7.1 Hz,2H), 3.28-3.22 (m, 4H), 3.08-2.97 (m, 1H), 2.75 (t, J = 7.5 Hz, 2H),2.10-1.96 (m, 5H), 1.81 (d, J = 12.2 Hz, 2H), 1.37 (dd, J = 24.7, 12.3Hz, 2H), 1.23 (dd, J = 25.1, 11.0 Hz, 2H); MS m/z 526.40 (M + 1). 42

UNC595A 1:0 +++ ¹H NMR (400 MHz, CD₃OD) δ 9.09 (s, 1H), 8.76 (d, J = 1.9Hz, 1H), 8.20 (dd, J = 8.9, 2.4 Hz, 1H), 7.08 (d, J = 9.0 Hz, 1H), 4.23(d, J = 7.1 Hz, 2H), 4.03-3.90 (m, 4H), 3.88 (bs, 1H), 3.58-3.47 (m,2H), 3.43-3.33 (m, 4H), 2.22-1.95 (m, 2H), 1.81-1.65 (m, 4H), 1.61- 1.37(m, 7H), 1.05-0.93 (m, 3H); MS m/z 465.40 (M + 1). 43

UNC593A 1:0 ++++ ¹H NMR (400 MHz, CD₃OD) δ 9.08 (s, 1H), 7.89 (d, J =8.9 Hz, 2H), 7.16 (d, J = 8.9 Hz, 2H), 4.22 (d, J = 7.1 Hz, 2H), 3.88(bs, 1H), 3.62-3.47 (m, 6H), 3.44-3.35 (m, 4H), 2.14 (bs, 1H), 1.81-1.65 (m, 4H), 1.62-1.35 (m, 8H), 1.01 (t, J = 7.4 Hz, 3H); MS m/z 464.40(M + 1). 44

UNC594A 1:0 +++ ¹H NMR (400 MHz, CD₃OD) δ 9.05 (s, 1H), 7.84 (d, J = 8.8Hz, 2H), 7.09 (d, J = 8.8 Hz, 2H), 4.21 (d, J = 7.1 Hz, 2H), 3.91 3.83(m, 5H), 3.52 (t, J = 7.1 Hz, 2H), 3.28- 3.18 (m, 4H), 2.14 (s, 1H),1.81-1.64 (m, 4H), 1.63- 1.36 (m, 8H), 1.00 (t, J = 7.4 Hz, 3H); MS m/z465.40 (M + 1). 45

UNC602A 0:1 +++ ¹H NMR (400 MHz, CD₃OD) δ 8.98 (s, 1H), 8.00-7.89 (m,2H), 7.23 (dd, J = 12.2, 5.4 Hz, 2H), 4.15 (d, J = 7.0 Hz, 2H),3.51-3.44 (m, 3H), 2.07- 1.89 (m, 3H), 1.75-1.60 (m, 4H), 1.51-1.41 (m,2H), 1.30-1.09 (m, 4H), 0.99 (t, J = 7.4 Hz, 3H); MS m/z 398.30 (M + 1).46

UNC603A 0:1 ++++ ¹H NMR (400 MHz, CD₃OD) δ 9.05 (s, 1H), 7.88 (d, J =8.8 Hz, 2H), 7.16 (d, J = 8.9 Hz, 2H), 4.16 (d, J = 7.0 Hz, 2H),3.65-3.43 (m, 7H), 3.43- 3.35 (m, 4H), 2.08-1.85 (m, 3H), 1.78-1.60 (m,4H), 1.46 (dq, J = 14.5, 7.4 Hz, 2H), 1.32-1.06 (m, 4H), 0.99 (t, J =7.4 Hz, 3H); MS m/z 464.30 (M + 1). 47

UNC600A N/A +++ ¹H NMR (400 MHz, CD₃OD) δ 9.04 (s, 1H), 8.03-7.90 (m,2H), 7.32- 7.18 (m, 2H), 4.30 (d, J = 6.6 Hz, 2H), 3.49 (t, J = 7.1 Hz,2H), (m, 2H), 2.98 (td, J = 12.8, 2.6 Hz, 2H), 2.45-2.34 (, 1H), 1.93(d, J = 12.7 Hz, 2H), 1.73- 1.51 (m, 4H), 1.45 (dq, J = 14.4, 7.3 Hz,2H), 0.99 (t, J = 7.4 Hz, 3H); MS m/z 383.30 (M + 1). 48

UNC606A N/A +++ ¹H NMR (400 MHz, CD₃OD) δ 9.11 (s, 1H), 8.75 (d, J = 2.1Hz, 1H), 8.20 (dd, J = 9.0, 2.4 Hz, 1H), 7.08 (d, J = 9.0 Hz, 1H), 4.30(d, J = 6.7 Hz, 2H), 3.99-3.90 (m, 4H), 3.52 (t, J = 7.1 Hz, 2H),3.46-3.38 (m, 2H), 3.38- 3.32 (m, 4H), 3.07-2.91 (m, 2H), 2.47-2.34 (m,1H), 1.94 (d, J = 12.6 Hz, 2H), 1.68 (dt, J = 14.6, 7.2 Hz, 2H), 1.57(dd, J = 19.4, 8.0 Hz, 2H), 1.46 (dq, J = 14.5, 7.3 Hz, 2H), 0.99 (t, J= 7.4 Hz, 3H); MS m/z 450.40 (M + 1). 49

UNC601A N/A ++++ ¹H NMR (400 MHz, CD₃OD) δ 9.05 (s, 1H), 7.88 (d, J =8.9 Hz, 2H), 7.16 (d, J = 8.9 Hz, 2H), 4.29 (d, J = 6.7 Hz, 2H),3.59-3.46 (m, 6H), 3.45- 3.37 (m, 6H), 3.04-2.94 (m, 2H), 2.45-2.31 (m,1H), 1.93 (d, J = 12.4 Hz, 2H), 1.73-1.53 (m, 4H) 1.46 (dq, J = 14.4,7.3 Hz, 2H), 0.99 (t, J = 7.4 Hz, 3H); MS m/z 449.40 (M + 1). 50

UNC596A 1:0 — ¹H NMR (400 MHz, CD₃OD) δ 8.88 (s, 1H), 7.93-7.81 (m, 2H),7.35- 7.27 (m, 2H), 7.25-7.11 (m, 5H), 5.41 (bs, 1H), 4.20 (d, J = 7.3Hz, 2H), 3.97 (s, 1H), 3.61-3.46 (m, 2H), 2.83-2.67 (m, 2H), 2.14 (bs,1H), 2.07- 1.95 (m, 2H), 1.83-1.38 (m, 9H); MS m/z 460.30 (M + 1). 51

UNC599A 1:0 +++ ¹H NMR (400 MHz, CD₃OD) δ 9.07 (s, 1H), 8.74 (d, J = 2.1Hz, 1H), 8.19 (dd, J = 8.9, 2.4 Hz, 1H), 7.30-7.20 (m, 4H), 7.18-7.12(m, 1H), 7.07 (d, J = 9.0 Hz, 1H), 4.19 (d, J = 7.1 Hz, 2H), 3.98- 3.90(m, 4H), 3.88 (s, 1H), 3.53 (t, J = 7.1 Hz, 2H), 3.40-3.32 (m, 4H), 2.74(t, J = 7.5 Hz, 2H), 2.11 (bs, 1H), 2.07-1.95 (m, 2H), 1.81-1.71 (m,2H), 1.62-1.38 (m, 6H); MS m/z 527.40 (M + 1). 52

UNC597A 1:0 +++ ¹H NMR (400 MHz, CD₃OD) δ 9.04 (s, 1H), 7.88 (d, J = 8.9Hz, 2H), 7.30-7.18 (m, 4H), 7.19- 7.13 (m, 3H), 4.18 (d, J = 7.1 Hz,2H), 3.87 (bs, 1H), 3.58-3.50 (m, 6H), 3.45- 3.35 (m, 4H), 2.74 (t, J =7.6 Hz, 2H), 2.11 (bs, 1H), 2.06-1.95 (m, 2H), 1.81- 1.70 (m, 2H),1.62-1.35 (m, 6H); MS m/z 526.40 (M + 1). 53

UNC598A 1:0 ++ ¹H NMR (400 MHz, CD₃OD) δ 9.01 (s, 1H), 7.83 (d, J = 8.9Hz, 2H), 7.34-7.20 (m, 4H), 7.16 (t, J = 6.9 Hz, 1H), 7.08 (d, J = 8.9Hz, 2H), 4.17 (d, J = 7.1 Hz, 2H), 3.91-3.83 (m, 5H), 3.51 (t, J = 7.2Hz, 2H), 3.28-3.19 (m, 4H), 2.74 (t, J = 7.6 Hz, 2H), 2.11 (bs, 1H),2.07- 1.95 (m, 2H), 1.81-1.71 (m, 2H), 1.63-1.36 (m, 6H); MS m/z 526.30(M + 1). 54

UNC604A 0:1 +++ ¹H NMR (400 MHz, CD₃OD) δ 8.87 (s, 1H), 7.90-7.83 (m,2H), 7.33- 7.26 (m,, 2H), 7.25-7.15 (m, 5H), 4.14 (d, J = 7.1 Hz, 2H),3.63-3.45 (m, 3H), 2.76 (t, J = 8.0 Hz, 2H), 2.08-1.93 (m, 5H), 1.72 (d,J = 12.7 Hz, 2H), 1.20 (tt, J = 23.8, 11.9 Hz, 4H); MS m/z 460.30 (M +1). 55

UNC605A 0:1 ++++ ¹H NMR (400 MHz, CD₃OD) δ 9.05 (s, 1H), 7.87 (d, J =8.8 Hz, 2H), 7.30-7.20 (m, 4H), 7.21- 7.12 (m, 3H), 4.12 (d, J = 6.8 Hz,2H), 3.60-3.44 (m, 7H), 3.43-3.34 (m, 4H), 2.73 (t, J = 7.5 Hz, 2H),2.01 (dt, J = 14.7, 7.4 Hz, 2H), 1.98-1.85 (m, 3H), 1.68 (d, J = 12.7Hz, 2H), 1.17 (tt, J = 23.9, 11.8 Hz, 4H); MS m/z 526.40 (M + 1). 56

UNC1056A 1:0 +++ ¹H NMR (400 MHz, CD₃OD) δ 9.07 (s, 1H), 7.83 (d, J =8.8 Hz, 2H), 7.08 (d, J = 8.8 Hz, 2H), 4.69-4.56 (m, 1H), 3.91- 3.82 (m,4H), 3.78 (dd, J = 13.3, 6.2 Hz, 2H), 3.76- 3.66 (m, 1H), 3.29-3.20 (m,4H), 2.70-2.54 (m, 2H), 2.29-1.99 (m, 6H), 1.60-1.45 (m, 2H); MS m/z491.3 (M + 1). 57

UNC1057A 0:1 +++ ¹H NMR (400 MHz, CD₃OD) δ 9.08 (s, 1H), 7.87 (d, J =8.9 Hz, 2H), 7.10 (d, J = 8.8 Hz, 2H), 4.75-4.63 (m, 1H), 4.08- 4.01 (m,1H), 3.92-3.83 (m, 4H), 3.83-3.75 (m, 2H), 3.30-3.22 (m, 4H), 2.70-2.47(m, 4H), 2.07- 1.96 (m, 2H), 1.87-1.71 (m, 4H) ); MS m/z 491.2 (M + 1).58

UNC1067A 0:1 +++ ¹H NMR (400 MHz, CD₃OD) δ 9.06 (s, 1H), 7.87 (d, J =8.8 Hz, 2H), 7.12 (d, J = 8.7 Hz, 2H), 4.76-4.65 (m, 1H), 4.35- 4.21 (m,2H), 3.92-3.82 (m, 4H), 3.77 (tt, J = 11.0, 4.3 Hz, 1H), 3.31-3.20 (m,4H), 2.30-2.20 (m, 1H), 2.17-1.89 (m, 5H), 1.60-1.45 (m, 1H), 1.41- 1.28(m, 1H); MS m/z 477.0 (M + 1). 59

UNC782A 0:1 ++ ¹H NMR (400 MHz, CD₃OD) δ 8.89 (s, 1H), 7.90-7.81 (m,2H), 7.18 (t, J = 8.7 Hz, 2H), 4.14 (d, J = 7.0 Hz, 2H), 3.67-3.55 (m,1H), 3.46 (t, J = 7.1 Hz, 2H), 2.04-1.85 (m, 6H), 1.71 (d, J = 11.4 Hz,2H), 1.64 (dt, J = 14.8, 7.4 Hz, 2H), 1.43 (dq, J = 14.4, 7.3 Hz, 2H),1.27- 1.09 (m, 4H), 0.96 (t, J = 7.4 Hz, 3H); MS m/z 439.3 (M + 1). 60

UNC783A 0:1 ++ ¹H NMR (400 MHz, CDCl₃ + CD₃OD) δ 8.98 (s, 1H), 7.94-7.84(m, 2H), 7.25-7.15 (m, 2H), 4.16 (d, J = 6.9 Hz, 2H), 3.49 (t, J = 7.1Hz, 2H), 3.22-3.11 (m, 1H), 2.91 (s, 3H), 2.01 (m, 3H), 1.75 (d, J =11.9 Hz, 2H), 1.66 (dt, J = 14.8, 7.4 Hz, 2H), 1.44 (dq, J = 14.5, 7.3Hz, 2H), 1.34- 1.14 (m, 4H), 0.97 (t, J = 7.4 Hz, 3H); MS m/z 475.3 (M +1). 61

UNC888A 0:1 +++ ¹H NMR (400 MHz, CD₃OD) δ 9.10 (s, 1H), 7.97 (dd, J =8.7, 5.3 Hz, 2H), 7.26 (t, J = 8.7 Hz, 2H), 4.22 (d, J = 6.8 Hz, 2H),3.82-3.74 (m, 2H), 3.51 (t, J = 7.1 Hz, 2H), 3.17-3.05 (m, 3H), 2.17 (d,J = 10.8 Hz, 2H), 2.13- 2.02 (m, 1H), 1.88 (d, J = 12.3 Hz, 2H), 1.68(dt, J = 14.8, 7.3 Hz, 2H), 1.54- 1.36 (m, 4H), 1.35-1.20 (m, 2H), 1.00(t, J = 7.4 Hz, 3H); MS m/z 441.3 (M + 1). 62

UNC886A 0:1 +++ ¹H NMR (400 MHz, CD₃OD) δ 9.05 (s, 1H), 7.83 (d, J = 8.7Hz, 2H), 7.08 (d, J = 8.7 Hz, 2H), 4.20 (d, J = 6.8 Hz, 2H), 3.93-3.80(m, 4H), 3.58 (t, J = 7.0 Hz, 2H), 3.28-3.19 (m, 4H), 3.11-2.99 (m, 1H),2.38-2.21 (m, 2H), 2.05 (d, J = 8.8 Hz, 3H), 1.96 (dt, J = 14.6, 7.2 Hz,2H), 1.83 (d, J = 12.1 Hz, 2H), 1.47-1.17 (m, 4H); MS m/z 518.3 (M + 1).63

UNC887A 0:1 +++ ¹H NMR (400 MHz, CD₃OD) δ 9.00 (s, 1H), 7.82 (d, J = 8.8Hz, 2H), 7.29-7.18 (m, 2H), 7.08 (d, J = 8.8 Hz, 2H), 7.03- 6.95 (m,2H), 4.14 (d, J = 6.8 Hz, 2H), 3.91-3.79 (m, 4H), 3.49 (t, J = 7.1 Hz,2H), 3.28-3.18 (m, 4H), 3.10-2.94 (m, 1H), 2.73 (t, J = 7.5 Hz, 2H),2.00 (dt, J = 14.5, 7.9 Hz, 5H), 1.80 (d, J = 12.2 Hz, 2H), 1.37 (dd, J= 23.5, 11.0 Hz, 2H), 1.21 (dd, J = 25.2, 11.1 Hz, 2H); MS m/z 544.4(M + 1).

Example 41-((trans-4-Aminocyclohexyl)methyl)-N-methyl-3-phenyl-1H-pyrazolo[3,4-d]pyrimidin-6-amineGeneral Procedure B:

6-(Methylthio)-3-phenyl-1H-pyrazolo[3,4-d]pyrimidine

A microwave tube was charged with3-bromo-6-(methylthio)-1H-pyrazolo[3,4-d]pyrimidine (1.0 g, 4.0 mmol),phenylboronic acid (1.5 g, 12 mmol), potassium phosphonate (2.5 g, 12mmol), tetrakis(triphenylphosphine)palladium (0.35 g, 0.30 mmol),dioxane (16 mL) and water (4 mL). The mixture was heated in microwave at150° C. for 20 min. The reaction mixture was poured into water. Theaqueous layer was extracted with EtOAc (10×). The combined organic layerwas dried (Na₂SO₄), concentrated, and purified to provide6-(methylthio)-3-phenyl-1H-pyrazolo[3,4-d]pyrimidine (0.85 g, 87%) as awhite solid. MS m/z 243.1 [M+H]⁺.

tert-Butyltrans-4-((6-(methylthio)-3-phenyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)cyclohexylcarbamate

To a suspension of trans-4-aminocyclohexanecarboxylic acid (5.0 g, 35mmol) in methanol (50 mL) was added thionyl chloride (2.9 mL, 40 mmol)dropwisely at 0° C. The white suspension was dissolved. After beingstirred at room temperature for 4.5 h, the solution was concentrated andwhite solid was obtained. Methylene chloride was added and thenevaporated twice to remove trace amount of thionyl chloride. Asuspension of the solid in methylene chloride (60 mL) was added triethylamine (5.4 mL, 38 mmol). A clear solution was obtained. The solution wascooled to 0° C. and Boc anhydride (8.83 mL, 38 mmol) was added slowly.The reaction mixture was stirred at room temperature for 5 h, thenpoured into an aqueous sodium bicarbonate solution. The mixture wasextracted with methylene chloride (3×), dried (Na₂SO₄), andconcentrated. The crude mixture was purified by Isco to givetrans-methyl 4-(tert-butoxycarbonylamino)cyclohexane carboxylate (9.0 g,100%) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 4.37 (s, 1H), 3.66 (s,3H), 3.44 (d, J=27.3 Hz, 1H), 2.22 (tt, J=12.1, 3.4 Hz, 1H), 2.03 (dd,J=24.0, 13.2 Hz, 4H), 1.56-1.47 (m, 2H), 1.45 (d, J=12.2 Hz, 9H), 1.10(qd, J=12.7, 3.1 Hz, 2H). ¹³C NMR (100 MHz, CDCl₃) δ 175.8, 155.1, 79.2,77.3, 77.0, 76.7, 51.6, 49.0, 42.4, 32.5, 28.4, 27.8.

A solution of trans-methyl4-(tert-butoxycarbonylamino)cyclohexanecarboxylate (9.0 g, 35 mmol) inTHF (70 mL) was added slowly a 2.0 M solution of LiAH₄ in THF (20 mL, 40mmol) at −78° C. The reaction was warmed slowly to room temperature(over 4 h), and quenched by dropwise addition of water (5 mL), followedby addition of NaOH (5 mL) and Na₂SO₄. The mixture was stirred for 20min and filtered. The filtrate was dried (Na₂SO₄), and concentrated. Thecrude mixture was purified by Isco to provide tert-butyltrans-4-(hydroxymethyl)cyclohexylcarbamate (5.5 g, 69%) as a whitesolid.

A solution of tert-butyl trans-4-(hydroxymethyl)cyclohexylcarbamate (5.5g, 24 mmol) and carbon tetrabromide (9.9 g, 30 mmol) in methylenechloride (120 mL) was added triphenylphosphine (7.5 g, 29 mmol) in threeportions at 0° C. The solution was stirred at room temperature for 4 h.After evaporation of solvent, a mixture of EtOAc and hexanes (1:1) wasadded. The resulting white solid was filtered off. The filtrate wasconcentrated and purified by Isco to provide tert-butyltrans-4-(bromomethyl)cyclohexyl carbamate (6.5 g, 93%) as a white solid.¹H NMR (400 MHz, CD₃OD) δ 3.31 (d, J=6.4 Hz, 2H), 3.25 (dd, J=15.0, 6.9Hz, 1H), 1.91 (d, J=9.6 Hz, 4H), 1.64-1.50 (m, 1H), 1.42 (s, 9H),1.28-1.05 (m, 4H); ¹³C NMR (100 MHz, CD₃OD) δ 157.8, 79.8, 50.8, 40.7,40.3, 33.4, 31.4, 28.8.

A microwave tube was charged with6-(methylthio)-3-phenyl-1H-pyrazolo[3,4-d]pyrimidine (0.073 g, 0.30mmol), potassium carbonate (0.14 g, 0.90 mmol), and DMSO (1 mL). Theresulting mixture was stirred for 20 min, then was added a solution oftert-butyl trans-4-(bromomethyl)cyclohexylcarbamate (0.10 g, 0.36 mmol)in THF (2 mL). The resulting mixture was heated at 150° C. for 10 min inmicrowave. The reaction mixture was poured into water and extracted withEt₂O (3×). The combined ether layer was dried (Na₂SO₄) and concentrated.The crude mixture was purified by Isco to provide tert-butyltrans-4-((6-(methylthio)-3-phenyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)cyclohexylcarbamate(0.12 g, 88%) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 9.11 (s, 1H),7.90 (d, J=7.2 Hz, 2H), 7.55-7.44 (t, J=6.8 Hz, 2H), 7.41 (t, J=7.3 Hz,1H), 4.37 (bs, 1H), 4.27 (d, J=7.1 Hz, 2H), 3.37 (bs, 1H), 2.61 (s, 3H),2.09-1.89 (m, 3H), 1.67 (d, J=12.1 Hz, 2H), 1.39 (s, 9H), 1.19 (dd,J=24.4, 10.8 Hz, 2H), 1.04 (ddd, J=25.4, 12.7, 2.9 Hz, 2H); ¹³C NMR (100MHz, CDCl₃) δ 170.1, 155.3, 154.8, 152.3, 144.3, 132.2, 129.2, 127.1,109.3, 79.3, 52.5, 49.7, 37.7, 32.9, 29.6, 28.5, 12.5; MS m/z 454.2[M+H]⁺.

tert-Butyltrans-4-((6-(methylamino)-3-phenyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)cyclohexylcarbamate

To a solution of tert-butyltrans-4-((6-(methylthio)-3-phenyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)cyclohexylcarbamate(0.14 g, 0.3 mmol) in methylene chloride (5 mL) was addedmeta-chloroperoxybenzoic acid (0.20 g, 0.9 mmol) at room temperature.After stirring at room temperature for 2 h, the light purple solutionwas quenched with a 1.0 N aqueous solution of NaOH. The aqueous layerwas extracted with EtOAc (3×). The organic layers were combined, dried(Na₂SO₄), and concentrated. The residue was dissolved in THF (1.5 mL),followed by the addition of a 2.0 M methylamine solution in THF (1.5 mL,3.0 mmol). The resulting solution was heated at 60° C. for 2 h, cooledto room temperature, and concentrated. The crude mixture was purified byIsco to provide tert-butyltrans-44(6-(methylamino)-3-phenyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)cyclohexylcarbamate (0.10 g, 76%) as a white solid.

1-((trans-4-Aminocyclohexyl)methyl)-N-methyl-3-phenyl-1H-pyrazolo[3,4-d]pyrimidin-6-amine

To a solution of tert-butyltrans-4-((6-(methylamino)-3-phenyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)cyclohexylcarbamate(0.082 g, 0.19 mmol) in methylene chloride (3 mL) was addedtrifluoroacidic acid (0.60 mL) The reaction mixture was stirred at roomtemperature for 2 h, concentrated and basified by a 7.0 M aqueoussolution of ammonia to pH 12. After evaporation, the residue waspurified by Isco to provide1-((trans-4-aminocyclohexyl)methyl)-N-methyl-3-phenyl-1H-pyrazolo[3,4-d]pyrimidin-6-amine(UNC00000545A) (0.051 g, 80%) as a white solid. ¹H NMR (400 MHz, CD₃OD)δ 8.94 (s, 1H), 7.94-7.83 (m, 2H), 7.55-7.44 (m, 2H), 7.44-7.36 (m, 1H),4.16 (d, J=7.5 Hz, 2H), 3.06-2.91 (m, 1H), 2.99 (s, 3H), 2.13-1.93 (m,3H), 1.78 (d, J=12.7 Hz, 2H), 1.45-1.14 (m, 4H); ¹³C NMR (100 MHz,CD₃OD) δ 162.87, 157.72, 154.93, 145.73, 133.64, 130.01, 129.95, 127.97,52.28, 51.32, 49.64, 49.43, 49.21, 49.00, 48.79, 48.57, 48.36, 38.38,31.91, 29.71, 28.52; MS m/z 337.3 [M+H]⁺.

Table 3 describes compounds prepared following procedures described inExample 4 (General Procedure B), using appropriate reagents.

TABLE 3 Physical Data MS m/z (M + 1) or/and dr Mer ¹H NMR (400 MHz,Structure Compound_ID cis:trans IC₅₀ CD₃OD)  1

UNC00000544A   1:0 ++ ¹H NMR (400 MHz, CD₃OD) δ 8.94 (s, 1H), 7.87 (d, J= 6.8 Hz, 2H), 7.48 (dd, J = 7.4, Hz, 2H), 7.41 (t, J = 7.3 Hz, 1H),4.30 (d, J = 7.6 Hz, 2H), 3.06 (dt, J = 11.7, 5.9 Hz, 1H), 3.00 (s, 3H),2.36- 2.24 (m, 1H), 1.76-1.71 (m, 4H), 1.64-1.45 (m, 4H); MS m/z 337.30(M + 1).  2

UNC00000171A N/A ++ ¹H NMR (300 MHz, CD₃OD) δ 8.98 (s, 1H), 7.92 (d, J =8.2 Hz, 2H), 7.62-7.33 (m, 3H), 4.31 (d, J = 6.8 Hz, 2H), 3.39 (d, J =13.1 Hz, 2H), 3.00 (s, 3H), 3.05-2.88 (m, 2H), 2.38 (bs, 1H), 1.91 (d, J= 12.2 Hz, 2H), 1.58 (dd, J = 23.0, 12.0 Hz, 2H); MS m/z 323.20 (M + 1). 3

UNC00000263A N/A ++ ¹H NMR (400 MHz, CD₃OD) δ 9.06 (s, 1H), 7.92 (d, J =7.3 Hz, 2H), 7.56-7.40 (m, 3H), 4.47-4.21 (m, 2H), 3.35 (t, J = 12.4 Hz,2H), 3.04 (s, 3H), 2.89 (dd, J = 22.3, 10.2 Hz, 2H), 2.50 (bs, 1H), 1.95(dd, J = 21.6, 8.5 Hz, 2H), 1.83-1.65 (m, 1H), 1.52-1.33 (m, 1H); MS m/z323.30 (M + 1).  4

UNC00000264A N/A + ¹H NMR (400 MHz, CD₃OD) δ 9.05 (s, 1H), 7.97 (d, J =12, 2H), 7.57-7.35 (m, 3H), 4.77 (dd, J = 15.0, 3.7 Hz, 1H), 4.56 (dd, J= 15.0, 8.4 Hz, 1H), 4.18-4.08 (m, 1H), 3.47-3.32 (m, 2H), 3.02 (s, 3H),2.38-2.30 (m, 1H), 2.17- 1.99 (m, 2H), 1.99-1.86 (m, 1H); MS m/z 309.20(M + 1).  5

UNC00000462A   1:0 ++ ms m/z 323.20 (M + 1).  6

UNC00000414A N/A ++ ¹H NMR (400 MHz, CD₃OD) δ 9.10 (s, 1H), 7.88 (d, J =8.0 Hz, 2H), 7.60-7.52 (d, 2H), 7.52-7.39 (m, 3H), 7.33 (dt, J = 19.3,9.7 Hz, 2H), 5.58 (s, 2H), 3.05 (s, 3H); MS m/z 331.20 (M + 1).  7

UNC00000415A N/A ++ ¹H NMR (400 MHz, CD₃OD) δ 9.09 (s, 1H), 7.98-7.88(m, 2H), 7.56-7.40 (m, 5H), 7.31 (s, 1H), 7.29-7.22 (m, 1H), 5.60 (s,2H), 3.04 (s, 3H); MS m/z 331.20 (M + 1).  8

UNC00000581A N/A ++ ¹H NMR (400 MHz, CD₃OD) δ 9.12 (s, 1H), 7.90 (d, J =7.3 Hz, 2H), 7.54-7.37 (m, 7H), 5.55 (s, 2H), 4.09 (s, 2H), 3.07 (s,3H); MS m/z 345.20 (M + 1).  9

UNC00000514A 2.2:1 ++ MS m/z 351.30 (M + 1). 10

UNC00000515A   0:1 ++ ¹H NMR (400 MHz, CD₃OD) δ 8.93 (s, 1H), 7.88 (d, J= 7.9 Hz, 2H), 7.47 (t, J = 7.6 Hz, 2H), 7.40 (t, J = 7.0 Hz, 1H), 4.18(d, J = 6.9 Hz, 2H), 3.04-2.90 (m, 1H), 2.98 (s, 3H), 2.64 (s, 3H),2.14-2.04 (m, 3H), 1.82 (d, J = 12.2 Hz, 2H), 1.44-1.11 (m, 5H); MS m/z351.30 (M + 1). 11

UNC00000516A   1:0 ++ ¹H NMR (400 MHz, CD₃OD) δ 9.17 (s, 1H), 7.95 (d, J= 7.8 Hz, 2H), 7.60-7.43 (m, 3H), 4.26 (d, J = 6.8 Hz, 2H), 3.20 (t, J =12.1 Hz, 1H), 3.07 (d, J = 5.9 Hz, 3H), 2.82 (s, 6H), 2.10 (d, J = 11.9Hz, 3H), 1.94 (d, J = 13.1 Hz, 2H), 1.53 (dd, J = 24.8, 12.7 Hz, 2H),1.32 (dd, J = 23.2, 12.0 Hz, 2H); MS m/z 365.30 (M + 1). 12

UNC00000568A   1:0 +++ ¹H NMR (400 MHz, CD₃OD) δ 8.92 (s, 1H), 8.00-7.85(m, 2H), 7.22 (t, J = 8.8 Hz, 2H), 4.19 (d, J = 7.2 Hz, 2H), 3.85 (s,1H), 3.45 (t, J = 7.1 Hz, 2H), 2.20-2.10 (m, 1H), 1.82-1.71 (m, 2H),1.70-1.60 (m, 2H), 1.59-1.32 (m, 8H), 0.98 (t, J = 7.4 Hz, 3H); MS m/z398.30 (M + 1). 13

UNC00000556A N/A + ¹H NMR (400 MHz, CD₃OD) δ 9.14-9.11 (m, 1H), 7.99-7.91 (m, 2H), 7.58-7.46 (m, 3H), 4.58 (t, J = 5.4 Hz, 2H), 4.07 (t, J =5.4 Hz, 2H), 3.78- 3.71 (m, 2H), 3.12-3.04 (m, 5H); MS m/z 313.20 (M +1). 14

UNC00000547A N/A ++ ¹H NMR (400 MHz, CD₃OD) δ 9.15 (s, 1H), 7.96 (d, J =7.2 Hz, 2H), 7.58-7.46 (m, 3H), 4.40 (t, J = 6.8 Hz, 2H), 3.08 (s, 3H),2.92 (t, J = 7.6 Hz, 2H), 2.09-1.99 (m, 2H), 1.79-1.69 (m, 2H), 1.54-1.42 (m, 2H); MS m/z 311.20 (M + 1). 15

UNC00000585A N/A ++ ¹H NMR (400 MHz, CD₃OD) δ 9.17 (s, 1H), 7.98-7.92(m, 2H), 7.56-7.46 (m, 3H), 4.43 (t, J = 6.6 Hz, 2H), 3.08 (s, 3H), 3.01(t, J = 7.7 Hz, 2H), 2.12-2.02 (m, 2H), 1.77-1.66 (m, 2H); MS m/z 297.20(M + 1). 16

UNC00000584A N/A ++ ¹H NMR (400 MHz, CD₃OD) δ 9.15 (s, 1H), 7.94 (dd, J= 1.4, 8.1 Hz, 2H), 7.56-7.46 (m, 3H), 4.37 (t, J = 6.9 Hz, 2H), 3.08(s, 3H), 2.90 (t, J = 7.6 Hz, 2H), 2.06-1.95 (m, 2H), 1.69-1.60 (m, 2H),1.53-1.38 (m, 4H); MS m/z 325.30 (M + 1). 17

UNC00000571A N/A ++ ¹H NMR (400 MHz, CD₃OD) ¹H NMR (400 MHz, cd₃od) δ9.08 (s, 1H), 7.94 (d, J = 7.1 Hz, 2H), 7.57-7.43 (m, 3H), 4.45 (t, J =6.7 Hz, 2H), 3.42- 3.34 (m, 2H), 3.04 (s, 3H), 2.97-2.86 (m, 2H), 2.13(d, J = 14.3 Hz, 2H), 1.98 (q, J = 6.7 Hz, 2H), 1.66-1.54 (m, 1H),154-1.38 (m, 2H); MS m/z 337.20 (M + 1).

Example 5tert-Butyl-4-((3-bromo-6-(methylthio)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)cyclohexylcarbamateGeneral Procedure C:

tert-Butyl-4-((3-bromo-6-(methylthio)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)cyclohexylcarbamate

A 10 mL microwave tube was charged with3-bromo-6-(methylthio)-1H-pyrazolo[3,4-d]pyrimidine (0.2 g, 0.8 mmol),potassium carbonate (0.34 g, 2.4 mmol), and DMSO (1.5 mL). The resultingmixture was stirred for 20 min, then tert-butyltrans-4-(bromomethyl)cyclohexylcarbamate (0.29 g, 1.0 mmol) and THF (3mL) were added. The resulting mixture was heated at 150° C. for 10 minin microwave. The reaction mixture was poured into water and extractedwith Et₂O (3×). The combined ether layers were dried (Na₂SO₄),concentrated, and purified by Isco to givetert-Butyl-4-((3-bromo-6-(methylthio)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)cyclohexylcarbamate (0.31 g, 85%) as a white solid. MS m/z 478.1 [M+Na]⁺.

tert-Butyl-4-((6-(methylthio)-3-phenyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)cyclohexylcarbamate

A microwave tube was charged with tert-butyltrans-4-((3-bromo-6-(methylthio)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)cyclohexylcarbamate(0.046 g, 0.1 mmol), phenylboronic acid (0.037 g, 0.3 mmol), potassiumphosphonate (0.063 g, 0.3 mmol), tetrakis(triphenylphosphine)palladium(0.012 g, 0.01 mmol), dioxane (2 mL) and water (0.5 mL) The mixture washeated in microwave at 150° C. for 10 min. The reaction mixture waspoured into water. The aqueous layer was extracted with Et₂O (3×). Thecombined organic layers were dried (Na₂SO₄), concentrated, and purifiedby Isco to givetert-Butyl-4-((6-(methylthio)-3-phenyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)cyclohexylcarbamate(0.040 g, 88%) as a white solid. MS m/z 454.3 [M+H]⁺.

tert-butyl4-((6-(methylamino)-3-phenyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)cyclohexylcarbamate

To a solution oftert-Butyl-4-((6-(methylthio)-3-phenyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)cyclohexylcarbamate(0.14 g, 0.3 mmol) in methylene chloride (5 mL) was addedmeta-chloroperoxybenzoic acid (0.20 g, 0.9 mmol) at room temperature.After stirring at room temperature for 2 h, the light purple solutionwas quenched with a 1.0 N aqueous solution of NaOH. The aqueous layerwas extracted with EtOAc (3×). The organic layers were combined, dried(Na₂SO₄), and concentrated. The residue was dissolved in THF (1 mL),followed by the addition of ethylamine (1.5 mL, 2.0 M in THF, 3 mmol).The resulting solution was heated at 60° C. for 2 h, cooled to roomtemperature, and concentrated. The crude mixture was purified by Isco toprovide tert-butyl4-((6-(methylamino)-3-phenyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)cyclohexylcarbamate(0.085 g, 81%) as a white solid.

1-((4-Aminocyclohexyl)methyl)-N-ethyl-3-phenyl-1H-pyrazolo[3,4-d]pyrimidin-6-amine

To a solution oftert-butyl-4-((6-(methylthio)-3-phenyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)cyclohexylcarbamate(0.045 g, 0.1 mmol) in methylene chloride (3 mL) was addedtrifluoroacetic acid (0.60 mL) The reaction mixture was stirred at roomtemperature for 2 h, concentrated and basified by a 7.0 M aqueoussolution of ammonia to pH 12. After evaporation, the residue waspurified by preparative HPLC to provide1-((4-aminocyclohexyl)methyl)-N-methyl-3-phenyl-1H-pyrazolo[3,4-d]pyrimidin-6-amine(UNC00000323A) (0.038 g, 82%) as a yellow solid (TFA salt). MS m/z 351.3[M+H]⁺.

Table 4 describes compounds prepared following procedures described inExample 5 (General Procedure C), using appropriate reagents.

TABLE 4 Physical Data MS m/z (M + 1) dr Mer or/and ¹H NMR (400 StructureCompound_ID cis:trans IC₅₀ MHz, CD₃OD)  1

UNC00000349A 1.3:1 + MS m/z 351.30 (M + 1).  2

UNC00000350A 1.5:1 + MS m/z 379.30 (M + 1).  3

UNC00000351A 1.6:1 + MS m/z 377.30 (M + 1).  4

UNC00000352A 1.7:1 + MS m/z 393.30 (M + 1).  5

UNC00000346A 1.7:1 +++ MS m/z 365.30 (M + 1).  6

UNC00000466A 1.7:1 ++ MS m/z 363.30 (M + 1).  7

UNC00000465A 1.8:1 +++ MS m/z 377.30 (M + 1).  8

UNC00000347A 1.7:1 +++ MS m/z 391.30 (M + 1).  9

UNC00000348A 1.8:1 ++ MS m/z 405.30 (M + 1). 10

UNC00000345A 1.6:1 + MS m/z 436.30 (M + 1). 11

UNC00000470A 1.8:1 + MS m/z 450.3 (M + 1). 12

UNC00000261A   1:0 ++ ¹H NMR (400 MHz, CD₃OD) δ 9.00 (s, 1H), 7.91 (d, J= 7.7 Hz, 2H), 7.50 (t, J = 7.4 Hz, 2H), 7.46-7.38 (m, 1H), 4.23 (d, J =7.2 Hz, 2H), 3.86 (s, 1H), 3.02 (s, 3H), 2.15 (bs, 1H), 1.84-1.66 (m,2H), 1.75-1.45 (m, 6H); MS m/z 338.20 (M + 1). 13

UNC00000262A   0:1 ++ ¹H NMR (400 MHz, CD₃OD) δ 9.08 (s, 1H), 7.94 (d, J= 7.4 Hz, 2H), 7.56-7.45 (m, 3H), 4.20 (d, J = 7.0 Hz, 2H), 3.49 (bs,1H), 3.05 (s, 3H), 2.10-1.87 (m, 3H), 1.72 (d, J = 11.1 Hz, 2H), 1.32-1.09 (m, 4H); MS m/z 338.20 (M + 1). 14

UNC00000343A 1.7:1 +++ MS m/z 365.30 (M + 1). 15

UNC00000344A 1.7:1 ++++ MS m/z 379.30 (M + 1). 16

UNC00000463A 1.7:1 +++ MS m/z 393.30 (M + 1). 17

UNC00000461A 1.7:1 − MS m/z 493.40 (M + 1). 18

UNC00000475A 1.8:1 ++++ MS m/z 407.3 (M + 1). 19

UNC00000464A 1.8:1 +++ MS m/z 421.40 (M + 1). 20

UNC00000467A 1.9:1 ++ MS m/z 395.30 (M + 1). 21

UNC00000468A 1.8:1 +++ MS m/z 395.30 (M + 1). 22

UNC00000469A 1.9:1 ++ MS m/z 381.30 (M + 1). 23

UNC00000473A 1.9:1 − Ms m/z 408.30 (M + 1). 24

UNC00000474A 1.6:1 + Ms m/z 422.40 (M + 1). 25

UNC00000573A   2:1 +++ MS m/z 441.30 (M + 1). 26

UNC00000472A 1.9:1 +++ MS m/z 427.30 (M + 1). 27

UNC00000471A 1.8:1 ++++ MS m/z 413.30 (M + 1). 28

UNC00000546A   2:1 +++ MS m/z 443.30 (M + 1). 29

UNC00000551A   2:1 ++++ MS m/z 427.30 (M + 1). 30

UNC00000554A 1.7:1 ++ MS m/z 489.30 (M + 1). 31

UNC00000550A   1:1 ++ MS m/z 481.30 (M + 1). 32

UNC00000549A 1.4:1 +++ MS m/z 431.30 (M + 1). 33

UNC00000555A   2:1 +++ MS m/z 438.30 (M + 1). 34

UNC00000574A   2:1 +++ MS m/z 471.30 (M + 1). 35

UNC00000552A   1:1 ++++ MS m/z 419.20 (M + 1). 36

UNC00000553A 1.5:1 +++ MS m/z 403.25 (M + 1). 37

UNC00000572A 1.5:1 +++ MS m/z 414.30 (M + 1). 38

UNC00000265A   1:0 ++ ¹H NMR (400 MHz, CD₃OD) δ 8.97 (s, 1H), 5.80 (s,1H), 5.48 (s, 1H), 4.19 (d, J = 7.1 Hz, 2H), 3.86 (s, 1H), 3.04 (s, 3H),2.20 (s, 3H), 2.10 (bs, 1H), 1.80-1.70 (m, 2H), 1.62-1.33 (m, 6H); MSm/z 302.20 (M + 1). 39

UNC00000266A   0:1 ++ ¹H NMR (400 MHz, CD₃OD) δ 8.94 (s, 1H), 5.79 (s,1H), 5.46 (s, 1H), 4.12 (d, J = 7.0 Hz, 2H), 3.55-3.45 (m, 1H), 3.02 (s,3H), 2.20 (s, 3H), 1.94 (d, J = 11.5 Hz, 3H), 1.67 (d, J = 12.0 Hz, 2H),1.29-1.05 (m, 4H); MS m/z 302.20 (M + 1). 40

UNC00000297A   1:0 + ¹H NMR (400 MHz, CD₃OD) δ 8.92 (s, 1H), 4.13 (d, J= 7.2 Hz, 2H), 3.86 (bs, 1H), 3.29-3.21 (m, 1H), 3.04 (d, J = 1.1 Hz,3H), 2.12-2.01 (m, 1H), 1.78-1.66 (m, 2H), 1.62-1.44 (m, 5H), 1.44- 1.32(m, 1H), 1.39 (d, J = 7.2 Hz, 6H); MS m/z 304.30 (M + 1). 41

UNC00000298A   0:1 + ¹H NMR (400 MHz, CD₃OD) δ 8.90 (s, 1H), 4.08 (d, J= 6.8 Hz, 2H), 3.54-3.40 (m, 1H), 3.29- 3.19 (m, 1H), 3.02 (s, 3H),2.00-1.83 (m, 3H), 1.65 (d, J = 12.8 Hz, 2H), 1.38 (d, J = 8.0 Hz, 6H)1.27-1.04 (m, 4H); MS m/z 304.20 (M + 1). 42

UNC00000267A N/A + ¹H NMR (400 MHz, CD₃OD) δ 8.98 (d, J = 1.0 Hz, 1H),5.81 (s, 1H), 5.48 (s, 1H), 4.33-4.22 (m, 2H), 3.03 (d, J = 1.1 Hz, 3H),2.95-2.83 (m, 3H), 2.51-2.38 (m, 1H), 2.20 (s, 3H), 2.05-1.84 (m, 3H),1.80-1.65 (m, 1H), 1.46-1.33 (m, 1H); MS m/z 287.20 (M + 1). 43

UNC00000299A N/A + ¹H NMR (400 MHz, CD₃OD) δ 8.97 (s, 1H), 4.31-4.16 (m,2H), 3.35- 3.25 (m, 3H), 3.05 (s, 3H), 2.96-2.81 (m, 2H), 2.44 (bs, 1H),1.93-1.73 (m, 2H), 1.72-1.57 (m, 1H), 1.45-1.32 (m, 1H), 1.39 (d, J =6.8 Hz, 6H); MS m/z 289.20 (M + 1). 44

UNC00000268A N/A + ¹H NMR (400 MHz, CD₃OD) δ 9.00 (s, 1H), 5.84 (s, 1H),5.49 (s, 1H), 4.74 (dd, J = 15.0, 3.7 Hz, 1H), 4.50 (dd, J = 15.0, 8.5Hz, 1H), 4.13-4.00 (m, 1H), 3.45-3.31 (m, 2H), 3.35-3.25 (m, 1H), 2.23(s, 3H), 2.14-1.99 (m, 2H), 1.92-1.80 (m, 1H); MS m/z 273.20 (M + 1). 45

UNC0000030A N/A + ¹H NMR (400 MHz, CD₃OD) δ 9.00 (s, 1H), 4.67 (dd, J =15.0, 3.8 Hz, 1H), 4.50 (dd, J = 15.0, 8.4 Hz, 1H), 4.16-4.02 (m, 1H),3.48-3.31 (m, 3H), 3.05 (d, J = 1.1 Hz, 3H), 2.37-2.23 (m, 1H),2.16-1.98 (m, 2H), 1.93- 1.80 (m, 1H), 1.41 (dd, J = 7.0, 1.1 Hz, 6H);MS m/z 275.20 (M + 1). 46

UNC00000269A   1:1 + MS m/z 303.30 (M + 1). 47

UNC00000270A N/A + ¹H NMR (400 MHz, CD₃OD) δ 9.01 (s, 1H), 4.23 (d, J =6.8 Hz, 1H), 4.14 (d, J = 6.9 Hz, 1H), 3.31-3.29 (m. 1H), 3.06 (s, 3H),2.34-2.25 (m, 1H), 2.09-1.96 (m, 2H), 1.88-1.73 (m, 2H), 1.65- 1.48 (m,2H), 1.39 (d, J = 7.0 Hz, 6H), 1.45-1.16 (m, 2H); MS m/z 289.20 (M + 1).48

UNC999A N/A + ¹H NMR (400 MHz, CDCl₃) δ 9.07 (s, H), 8.00-7.90 (m, 2H),7.77 (d, J = 7.8 Hz, 2H), 7.51 (t, 2H), 7.46-7.34 (m, 4H), 7.08 (t, J =7.4 Hz, 1H), 5.20-5.03 (m, 1H), 1.65 (d, J = 6.7 Hz, 6H); ¹³C NMR (100MHz, CDCl₃) δ 157.6, 154.4, 153.7, 143.9, 139.7, 132.9, 129.1, 129.1,128.8, 127.1, 122.7, 119.1, 108.0, 49.1, 22.0; MS m/z 330.2 (M + 1). 49

UNC1000A N/A − ¹H NMR (400 MHz, CDCl₃) δ 9.04 (s, 1H), 7.97-7.91 (m,2H), 7.68- 7.60 (m, 2H), 7.53-7.47 (m, 2H), 7.46-7.39 (m, 2H), 6.99-6.91(m, 2H), 5.14-5.01 (m, 1H), 3.84 (s, 3H), 1.63 (d, J = 6.7 Hz, 6H); ¹³CNMR (100 MHz, CDCl₃) δ 158.0, 155.6, 154.6, 153.6, 143.9, 133.0, 132.9,129.1, 128.8, 127.1, 121.2, 114.3, 107.7, 55.7, 48.9, 22.0; MS m/z 360.2(M + 1). 50

UNC1001A N/A − ¹H NMR (400 MHz, CDCl₃) δ 9.06 (s, 1H), 7.97-7.91 (m,2H), 7.74- 7.66 (m, 2H), 7.55-7.46 (m, 3H), 7.45-7.39 (m, 1H), 7.13-7.04(m, 2H), 5.14-5.04 (m, 1H), 1.64 (d, J = 6.7 Hz, 6H); ¹³C NMR (100 MHz,CDCl₃) δ 159.8, 157.7, 157.4, 154.4, 153.7, 144.0, 135.8, 135.7, 132.9,129.1, 128.9, 127.1, 120.9, 120.8, 115.8, 115.6, 108.0, 49.1, 22.0; MSm/z 348.2 (M + 1). 51

UNC1353A N/A ND ¹H NMR (400 MHz, CD₃OD) δ 9.07 (s, 1H), 8.01-7.93 (m,2H), 7.31- 7.22 (m, 2H), 4.22 (d, J = 6.8 Hz, 2H), 3.34 (d, J = 6.9 Hz,2H), 3.12-3.02 (m, 1H), 2.13-1.94 (m, 4H), 1.84 (d, J = 12.3 Hz, 2H),1.47-1.20 (m, 4H), 1.01 (d, J = 6.7 Hz, 6H); MS m/z 397.3 (M + 1). 52

UNC1354A N/A ND ¹H NMR (400 MHz, CD₃OD) δ 9.13 (s, 1H), 8.03-7.95 (m,2H), 7.31- 7.22 (m, 2H), 4.23 (d, J = 6.9 Hz, 2H), 3.63 (t, J = 6.4 Hz,2H), 3.56 (t, J = 7.0 Hz, 2H), 3.12-3.02 (m, 1H), 2.15-2.01 (m, 3H),1.89-1.72 (m, 4H), 1.71-1.60 (m, 2H), 1.47- 1.20 (m, 4H); MS m/z 413.50(M + 1).

Example 61-Cyclohexyl-3-phenyl-N-propyl-1H-pyrazolo[3,4-d]pyrimidin-6-amineGeneral Procedure D:

3-Bromo-N-propyl-1H-pyrazolo[3,4-d]pyrimidin-6-amine

To a mixture of 3-bromo-6-(methylthio)-1H-pyrazolo[3,4-d]pyrimidine(0.49 g, 2.0 mmol) in THF (5 mL) was added meta-chloroperoxybenzoic acid(0.52 g, 99%, 3 mmol) at room temperature. The white mixture was stirredfor 2 h and n-propylamine (0.82 mL, 10 mmol) was added at 0° C. Theresulting solution was heated at 40° C. for 12 h. After removal of thesolvent, MeOH was added and the mixture was filtered. The white solidwas washed with MeOH (3×) and dried to provide3-bromo-N-propyl-1H-pyrazolo[3,4-d]pyrimidin-6-amine (0.45 g, 88%) as awhite solid. ¹H NMR (400 MHz, DMSO-d6) δ 13.19 (bs, 1H), 8.63 (s, 1H),7.69 (bs, 1H), 3.29-3.17 (m, 2H), 1.61-1.49 (m, 2H), 0.88 (t, J=7.4 Hz,3H); ¹³C NMR (100 MHz, DMSO-d6) δ 161.61, 156.98, 152.71, 120.06,106.66, 42.68, 21.72, 11.47; MS m/z 256.1 [M+1].

1-Cyclohexyl-3-phenyl-N-propyl-1H-pyrazolo[3,4-d]pyrimidin-6-amine

A 10 mL microwave tube was charged with3-bromo-N-propyl-1H-pyrazolo[3,4-d]pyrimidin-6-amine (0.052 g, 0.2mmol), K₂CO₃ (0.14 g, 1.0 mmol), DMF (2 mL), and cyclohexyl chloride(0.072 g, 0.6 mmol). The resulting mixture was heated at 200° C. for 30minutes under microwave irradiation. After the reaction was cooled toroom temperature, phenylboronic acid (0.37 g, 0.3 mmol), Pd(PPh₃)₄(0.023 g, 0.02 mmol), and H₂O (1 mL) were added sequentially. Themixture was stirred at room temperature for 3 min and then heated at150° C. for 15 min. After cooled to room temperature, the mixture waspartitioned in H₂O and Et₂O. The aqueous phase was extracted with ether(3×). The combined organic phase were dried (Na₂SO₄) and concentrated.The residue was purified by Isco to provide the1-cyclohexyl-3-phenyl-N-propyl-1H-pyrazolo[3,4-d]pyrimidin-6-amine(UNC702A) (0.045 g, 67%) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ8.93 (s, 1H), 7.90 (d, J=8.0 Hz, 2H), 7.48 (t, J=6.0 Hz, 2H), 7.38 (t,J=6.0 Hz, 1H), 5.42 (s, 1H), 4.60 (tt, J=11.6, 4.1 Hz, 1H), 3.48 (dt,J=13.1, 6.8 Hz, 2H), 2.18-2.08 (m, 2H), 2.04-2.00 (m, 2H), 1.95-1.92 (m,2H), 1.77-1.74 (m, 1H), 1.74-1.65 (m, 2H), 1.58-1.42 (m, 2H), 1.40-1.28(m, 1H), 1.03 (t, J=7.4 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 160.73,155.38, 153.50, 143.71, 133.27, 129.06, 128.60, 127.09, 106.91, 56.10,43.68, 32.16, 25.91, 25.61, 22.98, 11.77; MS m/z 336.2 [M+1].

Table 5 describes compounds prepared following procedures described inExample 6 (General Procedure D), using appropriate reagents.

TABLE 5 Physical Data Mer MS m/z (M + 1) or/and Structure Compound_IDIC₅₀ ¹H NMR (400 MHz)  1

UNC703A ++ ¹H NMR (400 MHz, CDCl₃) δ 8.95 (s, 1H), 8.13 (d, J = 8.3 Hz,2H), 7.98 (d, J = 8.3 Hz, 2H), 5.48 (bs, 1H), 4.61 (tt, J = 11.5, 4.1Hz, 1H), 3.94 (s, 3H), 3.48 (dt, J = 12.6, 6.7 Hz, 2H), 2.16-2.06 (m,2H), 2.06-1.98 (m, 2H), 1.97- 1.90 (m, 2H), 1.80-1.73 (m, 1H), 1.74-1.64(m, 2H), 1.57-1.42 (m, 2H), 1.42-1.28 (m, 1H), 1.02 (t, J = 7.4 Hz, 3H);¹³C NMR (100 MHz, CDCl₃) δ 166.95, 160.60, 155.47, 153.22, 142.40,137.51, 130.30, 129.83, 126.69, 106.82, 56.17, 52.29, 43.61, 32.11,25.81, 25.52, 22.88, 11.69; MS m/z 394.0 (M + 1).  2

UNC705A ++++ ¹H NMR (400 MHz, CD₃OD + CD₂Cl₂ + several drops of NH₃CH₃OHsolution) δ 8.97 (s, 1H), 8.06 (d, J = 8.4 Hz, 2H), 7.92 (d, J = 8.4 Hz,2H), 4.66-4.58 (m, 1H), 3.44 (t, J = 7.1 Hz, 2H), 2.20-2.06 (m, 2H),2.03- 1.88 (m, 4H), 1.80-1.76 (m, 1H), 1.70 (tq, J = 7.1, 7.4 Hz, 2H),1.59-1.45 (m, 2H), 1.42-1.33 (m, 1H), 1.01 (t, J = 7.4 Hz, 3H); ¹³C NMR(100 MHz, CD₃OD + CD₂Cl₂ + several drops of NH₃CH₃OH solution) δ 174.84,161.91, 156.45, 154.76, 144.75, 139.20, 135.55, 130.77, 127.21, 107.31,57.22, 44.23, 32.94, 26.74, 26.49, 23.54, 11.85; MS m/z 380.2 (M + 1). 3

UNC704A +++ ¹H NMR (400 MHz, CDCl₃) δ 8.75 (s, 1H), 7.93 (s, 1H), 7.51(t, J = 1.6 Hz, 1H), 6.93 6.87 (d, J = 1.6 Hz, 1H), 5.38 (bs, 1H), 4.54(tt, J = 11.7, 4.0 Hz, 1H), 3.46 (dt, J = 13.1, 6.8 Hz, 2H), 2.15-2.03(m, 2H), 2.01-1.88 (m, 4H), 1.78-1.72 (m, 1H), 1.73- 1.63 (m, 2H),1.54-1.41 (m, 2H), 1.38-1.29 (m, 1H), 1.02 (t, J = 7.4 Hz, 3H); ¹³C NMR(100 MHz, CDCl₃) δ 160.84, 154.94, 152.67, 143.68, 140.02, 136.96,119.19, 109.06, 106.90, 56.13, 43.63, 32.02, 25.84, 25.52, 22.91, 11.69;MS m/z 326.2 (M + 1).  4

UNC706A ++ ¹H NMR (400 MHz, CDCl₃) δ 9.15 (s, 1H), 8.91 (s, 1H), 8.63(d, J = 4.9, 1H), 8.22 (d, J = 7.7 Hz, 1H), 7.42 (dd, J = 7.7, 4.9 Hz,1H), 5.54 (bs, 1H), 5.10-4.98 (m, 1H), 3.47 (dt, J = 13.2, 6.7 Hz, 2H),1.77-1.63 (m, 2H), 1.58 (d, J = 6.7 Hz, 6H), 1.02 (t, J =7.4 Hz, 3H);¹³C NMR (100 MHz, CDCl₃) δ 160.41, 155.33, 152.71, 149.49, 147.99,140.79, 134.18, 129.29, 123.99, 106.62, 48.73, 43.60, 22.82, 21.87,11.68; MS m/z 297.2 (M + 1).  5

UNC707A + ¹H NMR (400 MHz, CDCl₃) δ 8.80 (s, 1H), 7.75 (dd, J = 7.6, 1.6Hz, 1H), 7.41-7.34 (m, 1H), 7.08- 6.99 (m, 2H), 5.55 (bs, 1H), 4.20 (d,J = 7.1 Hz, 2H), 4.14-3.99 (m, 2H), 3.87 (s, 3H), 3.48-3.40 (m, 2H),2.68 (t, J = 11.9 Hz, 2H), 2.28-2.16 (m, 1H), 1.72-1.57 (m, 4H), 1.43(s, 9H), 1.34-1.22 (m, 2H), 1.00 (t, J = 7.4 Hz, 3H); ¹³C NMR (100 MHz,CDCl₃) δ 159.15, 156.76, 156.10, 154.93, 153.75, 143.05, 130.61, 130.46,121.80, 121.30, 111.39 107.39, 79.50, 55.56, 51.49, 43.59, 36.74, 29.87,28.58, 22.68, 11.68; MS m/z 481.3 (M + 1).  6

UNC708A + ¹H NMR (400 MHz, CD₃OD) δ 8.85 (s, 1H), 7.79 (d, J = 8.8 Hz,2H), 6.99 (d, J = 8.8 Hz, 2H), 4.40 (t, J = 6.7 Hz, 2H), 3.82 (s, 3H),3.44-3.35 (m, 2H), 3.00 (t, J = 6.8 Hz, 2H), 2.66-2.60 (m, 3H),1.79-1.73 (m, 4H), 1.72- 1.61 (m, 2H), 0.98 (t, J = 7.4 Hz, 3H); ¹³C NMR(100 MHz, CD₃OD) δ 162.20, 161.72, 157.35, 154.84, 145.77, 129.22,126.20, 115.32, 106.86, 55.80, 55.79, 55.02, 45.76, 44.25, 24.19, 23.58,11.88; MS m/z 381.3 (M + 1).  7

UNC709A + ¹H NMR (400 MHz, CDCl₃) δ 9.22 (d, J = 13.2 Hz, 3H), 8.89 (s,1H), 5.74 (s, 1H), 4.33 (t, J = 7.0 Hz, 2H), 3.63 (t, J = 6.5 Hz, 2H),3.44 (dd, J = 13.0, 6.7 Hz, 2H), 2.44 (bs, 1H), 2.06-1.88 (m, 2H), 1.73-1.56 (m, 4H), 1.49-1.35 (m, 2H), 0.99 (t, J = 7.4 Hz, 3H); ¹³C NMR (100MHz, CDCl₃) δ 160.95, 158.14, 156.19, 154.52, 152.81, 137.82, 127.32,106.00, 62.57, 46.48, 43.52, 32.27, 29.17, 23.01, 22.72, 11.63; MS m/z342.2 (M + 1).  8

UNC710A + ¹H NMR (400 MHz, CDCl₃+CD₂Cl₂) δ 8.92 (s, 1H), 8.00 (d, J =8.3 Hz, 2H), 7.73 (d, J = 8.2 Hz, 2H), 7.38 (d, J = 6.8 Hz, 2H),7.34-7.22 (m, 3H), 5.492 (bs, 1H), 5.49 (s, 2H), 3.47 (dt, J = 13.2, 6.6Hz, 2H), 1.76-1.59 (m, 2H), 1.00 (t, J = 7.4 Hz, 3H); ¹³C NMR (100 MHz,CDCl₃ + CD₂Cl₂) δ 160.97, 156.38, 153.04, 142.32, 137.13, 136.66,132.72, 128.65, 128.23, 127.89, 127.21, 118.78, 111.93, 106.16, 50.33,43.50, 22.68, 11.51; MS m/z 369.2 (M + 1).  9

UNC711A ++ ¹H NMR (400 MHz, CD₃OD) δ 9.22 (s, 1H), 8.85 (d, J = 5.1 Hz,2H), 8.75 (d, J = 2.2 Hz, 1H), 8.25 (dd, J = 9.1, 2.3 Hz, 1H), 8.00 (d,J = 6.2 Hz, 2H), 7.13 (d, J = 9.1 Hz, 1H), 5.88 (s, 2H), 4.03- 3.91 (m,4H), 3.44 (t, J = 7.1 Hz, 2H), 3.37 (m, 4H), 3.35 (s, 2H), 1.72-1.60 (m,2H), 0.98 (q, J = 7.3 Hz, 3H); ¹³C NMR (100 MHz, CD₃OD) δ 159.29,157.98, 146.44, 143.87, 138.08, 126.77, 120.24, 119.34, 117.41, 114.58,111.75, 109.34, 106.72, 49.85, 44.34, 44.19, 43.35, 23.10, 11.69; MS m/z430.3 (M + 1). 10

UNC978A ++++ ¹H NMR (400 MHz, CDCl₃) δ 8.76 (s, 1H), 7.76-7.72 (m, 2H),7.28- 7.24 (m, 2H), 4.56-4.48 (m, 1H), 3.71-3.61 (m, 1H), 3.42-3.39 (m,1H), 3.29-3.27 (m, 2H), 2.92 (s, 3H), 2.14-2.02 (m, 4H), 1.97-1.90 (m,2H), 1.61- 1.53 (m, 2H), 1.47-1.32 (m, 6H), 0.90 (t, J = 7.36 Hz, 3H);MS m/z 459.30 (M + 1). 11

UNC970A +++ ¹H NMR (400 MHz, CDCl₃) δ 9.27 (s, 1H), 8.83 (s, 1H), 7.94(s, 1H), 7.79 (d, J = 5.93 Hz, 2H), 7.38- 7.35 (m, 2H), 4.67-4.60 (m,1H), 3.53 (s, 2H), 3.06 (s, 3H), 2.56-2.48 (m, 1H), 2.36-2.32 (m, 1H),2.16- 1.97 (m, 4H), 1.86-1.68 (m, 4H), 1.49-1.40 (m, 3H), 0.97 (td, J =3.02, 7.30 Hz, 3H); MS m/z 459.20 (M + 1). 12

UNC971A ++++ ¹H NMR (400 MHz, CDCl₃) δ 8.95 (s, 1H), 8.04 (d, J = 8.61Hz, 2H), 7.97 (d, J = 8.59 Hz, 2H), 5.36 (brs, 1H), 4.67-4.64 (m, 1H),4.34 (d, J = 7.55 Hz, 1H), 3.87-3.80 (m, 1H), 3.52 (dd, J = 7.03, 12.98Hz, 2H), 3.24-3.15 (m, 1H), 2.28-2.18 (m, 4H), 2.09-2.06 (m, 2H), 1.82-1.79 (m, 2H), 1.67-1.56 (m, 6H), 1.52-1.46 (m, 4H), 1.27-1.14 (m, 6H),1.00 (t, J = 7.35 Hz, 3H); MS m/z 527.00 (M + 1). 13

UNC972A ++++ ¹H NMR (400 MHz, CDCl₃) δ 8.94 (s, 1H), 8.06-8.02 (m, 2H),7.99- 7.96 (m, 2H), 4.75-4.464 (m, 1H), 4.46 (d, J =7.69 Hz, 1H),3.53-3.51 (m, 2H), 3.24-3.16 (m, 1H), 2.59-2.49 (m, 1H), 2.41- 2.32 (m,1H), 2.20-2.12 (m, 1H), 2.04-1.96 (m, 4H), 1.87-1.81 (m, 4H), 1.69-1.62(m, 4H), 1.51- 1.43 (m, 4H), 1.27-1.13 (m, 6H), 0.99 (td, J = 0.99, 7.29Hz, 3H); MS m/z 527.00 (M + 1). 14

UNC973A ++++ ¹H NMR (400 MHz, CDCl₃) δ 8.85 (s, 1H), 8.02-7.97 (m, 4H),4.70- 4.64 (m, 1H), 4.47 (t, J = 6.18 Hz, 1H), 4.17 (s, 1H), 3.54 (t, J= 8.01 Hz, 2H), 3.01 (dd, J = 6.88, 13.39 Hz, 2H), 2.59-2.50 (m, 2H),2.04 (d, J = 14.14 Hz, 2H), 1.89-1.67 (m, 6H), 1.51-1.42 (m, 4H), 1.31(dq, J = 7.25, 14.31 Hz, 2H), 0.99 (t, J = 7.36 Hz, 3H), 0.87 (t, J =7.32 Hz, 3H)); MS m/z 501.00 (M + 1). 15

UNC974A ++++ ¹H NMR (400 MHz, CDCl₃) δ 8.85 (s, 1H), 8.00 (s, 4H),4.73-4.64 (m, 1H), 4.45 (t, J = 6.00 Hz, 1H), 3.92-3.84 (m, 1H), 3.54(s, 2H), 3.01 (dd, J = 6.85, 13.40 Hz, 2H), 2.56-1.99 (m, 6H), 1.88-1.77(m, 1H), 1.74-1.67 ((m, 2H), 1.52-1.42 (m, 5H), 1.34- 1.27 (m, 2H), 0.99(td, J = 1.22, 7.32 Hz, 3H), 0.87 (t, J = 7.32 Hz, 3H) ); MS m/z 501.00(M + 1). 16

UNC976A ++++ ¹H NMR (400 MHz, CDCl₃) δ 8.91 (s, 1H), 8.00 (dd, J = 8.62,20.77 Hz, 4H), 4.69-4.61 (m, 1H), 4.26 (d, J = 7.61 Hz, 1H), 3.88-3.80(m, 1H), 3.57- 3.48 (m, 2H ), 2.27-2.18 (m, 4H), 2.07 (d, J = 10.85 Hz,2H), 1.71-1.53 (m, 6H), 1.47 (dd, J = 7.36, 14.90 Hz, 2H), 1.11 (d, J =6.52 Hz, 6H), 0.99 (t, J = 7.34 Hz, 3H); MS m/z 487.30 (M + 1). 17

UNC977A ++++ ¹H NMR (400 MHz, CDCl₃) δ 8.86 (s, 1H), 8.00 (s, 4H),4.70-4.63 (m, 1H), 4.48 (d, J = 7.67 Hz, 1H), 4.17 (s, 1H), 3.58-3.50(m, 3H), 2.59-2.33 (m, 2H), 2.04 (d, J = 13.46 Hz, 2H), 1.88-1.67 (m,6H), 1.51- 1.42 (m, 2H), 1.12 (d, J = 6.53 Hz, 6H), 0.99 (t, J = 7.36Hz, 3H); MS m/z 487.30 (M + 1). 18

UNC979A ++++ ¹H NMR (400 MHz, CDCl₃) δ 8.73 (s, 1H), 7.71 (d, J = 8.28Hz, 4H), 7.25 (d, J = 7.44 Hz, 2H), 7.20 (d, J = 7.44 Hz, 2H), 6.83 (s,1H), 4.62-4.56 (m, 1H), 3.84-3.79 (m, 1H), 3.54- 3.50 (m, 2H), 2.38 (s,3H), 2.22-2.14 (m, 4H), 2.06- 2.00 (m, 2H), 1.72-1.65 (m, 2H), 1.60-1.54(m, 2H), 1.51-1.41 (m, 2H), 0.99 (td, J = 1.03, 7.25 Hz, 3H); MS m/z535.25 (M + 1). 19

UNC980A +++ ¹H NMR (400 MHz, CDCl₃) δ 8.69 (s, 1H), 7.73-7.67 (m, 4H),7.27- 7.19 (m, 4H), 7.02 (s, 1H), 4.68-4.64 (m, 1H), 3.90- 3.83 (m, 1H),3.54-3.49 (m, 2H), 2.38 (s, 3H), 2.31 (d, J = 12.05 Hz, 1H), 2.17-2.06(m, 2H), 2.01- 1.96 (m, 3H), 1.70 (dt, J = 7.46, 14.85 Hz, 2H), 1.50-1.37 (m, 4H), 0.98 (t, J = 7.35 Hz, 3H); MS m/z 535.25 (M + 1). 20

UNC983A ++++ ¹H NMR (400 MHz, CDCl₃) δ 8.87 (s, 1H), 8.02-7.96 (m, 4H),4.69- 4.60 (m, 1H), 4.35 (t, J = 6.09 Hz, 1H), 2.87-3.79 (m, 1H), 3.53(dd, J = 6.77, 11.90 Hz, 2H), 3.11-3.04 (m, 2H), 2.20-1.17 (m, 4H),2.09-2.06 (m, 2H), 1.88 (brs, 2H), 1.72-1.60 (m, 2H), 1.60-1.56 (m, 2H),1.47 (m, 2H), 1.14 (t, J = 7.24 Hz, 3H), 0.99 (t, J = 7.35 Hz, 3H); MSm/z 473.20 (M + 1). 21

UNC984A ++++ ¹H NMR (400 MHz, CDCl₃) δ 8.84 (s, 1H), 7.99 (s, 4H),4.70.4.64 (m, 1H), 4.50-4.47 (m, 1H), 4.17 (s, 1H), 3.88-3.85 (m, 1H),3.54 (s, 2H), 3.11-3.05 (m, 2H), 2.59-2.50 (m, 1H), 2.37-2.31 (m, 1H),2.17- 1.99 (m, 4H), 1.87-1.77 (m, 2H), 1.71 (dt, J = 6.98, 14.26 Hz,2H), 1.46 (dq, J = 7.31, 14.50 Hz, 2H), 1.14 (t, J = 7.23 Hz, 3H), 0.99(t, J = 7.34 Hz, 3H); MS m/z 473.20 (M + 1). 22

UNC986A ++++ ¹H NMR (400 MHz, CDCl₃) δ 9.44 (brs, 1H), 8.92 (s, 1H),8.00 (q, J = 8.67 Hz, 4H), 4.69-4.61 (m, 2H), 3.90-3.84 (m, 4H), 3.55(t, J = 7.04 Hz, 2H), 3.43-3.33 (m, 2H), 2.21-2.07 (m, 6I-1), 1.79- 1.68(m, 4H), 1.60-1.44 (m, 6H), 1.00 (t, J = 7.36 Hz, 3H); MS m/z 529.30(M + 1). 23

UNC987A ++++ ¹H NMR (400 MHz, CDCl₃) δ 8.91 (s, 1H), 8.06-7.97 (m, 4H),4.48 (d, J = 7.69 Hz, 1H), 3.90- 3.85 (m, 2H), 3.55-3.50 (m, 2H),3.45-3.33 (m, 4H), 2.55-2.49 (m, 1H), 2.35-2.32 (m, 1H), 2.04- 1.99 (m,4H), 1.87-1.77 (m, 4H), 1.71-1.64 (m, 3H), 1.53-1.41 (m, 4H), 0.99 (t, J= 7.36 Hz, 3H); MS m/z 529.30 (M + 1). 24

UNC1029A +++ ¹H NMR (400 MHz, CDCl₃) δ 9.38 (s, 1H), 8.82 (s, 1H),7.94-7.89 (m, 2H), 7.85-7.81 (m, 2H), 7.09- 7.05 (m, 2H), 6.98-6.94 (m,2H), 6.57 (s, 1H), 4.67-4.61 (m, 1H), 3.98- 3.80 (m, 1H), 3.57-3.51 (m,2H), 2.22-2.08 (m, 6H), 1.71 (dt, J = 7.29, 14.74 Hz, 2H), 1.62-1.57 (m,2H), 1.45 (dt, J = 7.37, 14.45 Hz, 2H), 0.99 (t, J = 7.38 Hz, 3H); MSm/z 539.30 (M + 1). 25

UNC1030A +++ ¹H NMR (400 MHz, CDCl₃) δ 8.90 (s, 1H), 7.96 (dd, J = 3.63,8.55 Hz, 2H), 7.81 (dd, J = 3.50, 8.53 Hz, 2H), 7.09-7.04 (m, 3H),6.96-6.91 (m, 2H), 4.73- 4.63 (m, 1H), 3.90-3.82 (m, 1H), 3.52 (s, 2H),2.56-2.45 (m, 1H), 2.38- 2.31 (m, 1H), 2.20-1.95 (m, 4H), 1.86-1.79 (m,2H), 1.68-1.62 (m, 2H), 1.50-1.40 (m, 3H), 0.98 (t, J = 7.33 Hz, 3H); MSm/z 539.30 (M + 1). 26

UNC1032A ++++ ¹H NMR (400 MHz, CDCl₃) δ 8.86 (s, 1H), 8.03-7.95 (m, 4H),7.26- 7.18 (m, 2H), 6.97 (t, J = 8.58 Hz, 2H), 4.74 (t, J = 6.03 Hz,1H), 4.68-4.66 (m, 1H), 4.17 (d, J = 6.11 Hz, 2H), 3.87-3.81 (m, 1H),3.54-3.53 (m, 2H), 2.26-2.20 (m, 4H), 2.10- 2.03 (m, 4H), 1.69 (dt, J =7.43, 14.85 Hz, 2H), 1.63- 1.54 (m, 1H), 1.52-1.44 (m, 2H), 0.99 (t, J =7.35 Hz, 3H); MS m/z 553.30 (M + 1). 27

UNC1033A ++++ ¹H NMR (400 MHz, CDCl₃) δ 9.45 (brs, 1H), 8.88 (s, 1H),7.97 (s, 4H), 7.20 (dd, J = 5.42, 8.37 Hz, 2H), 6.96 (t, J = 8.55 Hz,2H), 4.93 (s, 1H), 4.70- 4.65 (m, 1H), 4.18 (d, J = 5.60 Hz, 2H),3.91-3.86 (m, 1H), 3.55 (s, 2H), 2.60-2.51 (m, 1H), 2.36- 2.34 (m, 1H),2.19-2.00 (m, 3H), 1.88-1.81 (m, 2H), 1.72 (dt, J = 7.39, 14.89 Hz, 2H),1.46 (dd, J = 7.40, 14.91 Hz, 2H), 0.99 (t, J = 7.31 Hz, 3H); MS m/z553.30 (M + 1). 28

UNC1035A ++++ ¹H NMR (400 MHz, CDCl₃) δ 8.82 (s, 1H), 7.99 (q, J = 8.67Hz, 4H), 4.68- 4.64 (m, 1H), 4.44 (d, J = 7.34 Hz, 1H), 3.86-3.82 (m,1H), 3.67 (dd, J = 6.82, 13.53 Hz, 1H), 3.55-3.50 (m, 2H), 2.22-2.16 (m,4H), 2.10-2.07 (m, 2H), 1.84 (dd, J = 5.70, 12.36 Hz, 2H), 1.71 (dd, J =7.63, 14.79 Hz, 2H), 1.63- 1.57 (m, 4H), 1.54-1.48 (m, 4H), 1.40-1.35(m, 2H), 1.00 (t, J = 7.35 Hz, 3H); MS m/z 513.30 (M + 1). 29

UNC1036A ++++ ¹H NMR (400 MHz, CDCl₃) δ 8.90 (d, J = 4.54 Hz, 1H),8.02-7.97 (m, 4H), 4.76-4.63 (m, 2H), 3.91-3.83 (m, 1H), 3.65 (dq, J =6.83, 13.66 Hz, 1H), 3.53 (s, 2H), 2.59- 2.49 (m, 1H), 2.36-2.33 (m,1H), 2.18-1.97 (m, 4H), 1.88-1.76 (m, 4H), 1.71-1.61 (m, 4H), 1.55- 1.33(m, 6H), 0.98 (td, J = 0.93, 7.32 Hz, 3H); MS m/z 513.30 (M + 1). 30

UNC1039 +++ ¹H NMR (400 MHz, CDCl₃) δ 8.77 (s, 1H), 7.90-7.75 (m, 4H),7.07 (d, J = 8.40 Hz, 2H), 6.98 (d, J = 8.43 Hz, 2H), 6.38 (s, 1H),4.71-2.69 (m, 1H), 3.87-3.86 (m, 1H), 3.54- 3.52 (m, 2H), 2.29 (s, 3H),2.17-2.09 (m, 2H), 2.01- 1.97 (m, 4H), 1.85-1.76 (m, 2H), 1.74-1.66 (m,2H), 1.50-1.43 (m, 3H), 0.99 (td, J = 1.10, 7.33 Hz, 3H); MS m/z 535.30(M + 1). 31

UNC1059A ++++ ¹H NMR (400 MHz, CDCl₃) δ 8.83 (s, 1H), 7.98 (s, 4H),4.68-4.62 (m, 1H), 4.42 (t, , J = 6.16 Hz 1H), 3.87-3.81 (m, 1H), 3.57-3.51 (m, 2H), 2.98 (dd, J = 6.95, 13.46 Hz, 2H), 2.25- 2.16 (m, 4H),2.10-2.07 (m, 2H), 1.71 (dt, J = 7.43, 14.83 Hz, 2H), 1.60-1.42 (m, 6H),1.00 (t, J = 7.36 Hz, 3H), 0.89 (t, J = 7.40 Hz, 3H); MS m/z 487.30 (M +1). 32

UNC1061A ++++ ¹H NMR (400 MHz, CD₃OD) δ 9.11-9.09 (m, 1H), 8.18-8.14 (m,2H), 7.96 (d, J = 8.40 Hz, 2H), 4.74-4.69 (m, 1H), 4.04 (s, 1H),3.80-3.72 (m, 1H), 3.53-2.48 (m, 2H), 2.86 (t, J = 7.06 Hz, 2H), 2.58-2.48 (m, 1H), 2.41-2.25 (m, 1H), 2.10-1.95 (m, 4H), 1.84-1.78 (m, 2H),1.71-1.64 (m, 2H), 1.53- 1.38 (m, 4H), 1.00 (t, J = 7.36 Hz, 3H), 0.88(t, J = 7.40 Hz, 3H); MS m/z 487.30 (M + 1). 33

UNC866A +++ ¹H NMR (400 MHz, CD₃OD) δ 9.28 (s, 1H), 9.02 (s, 1H),7.99-7.91 (m, 2H), 7.80 (d, J = 8.5 Hz, 2H), 7.68 (d, J = 9.4 Hz, 1H),7.23 (t, J = 8.8 Hz, 2H), 5.70 (s, 2H), 3.49 (t, J = 7.1 Hz, 2H), 1.64(dt, J = 14.8, 7.3 Hz, 2H), 1.43 (dq, J = 14.6, 7.4 Hz, 2H), 0.95 (t, J= 7.4 Hz, 3H); MS m/z 416.2 (M + 1). 34

UNC842A +++ ¹H NMR (400 MHz, CD₃OD) δ 9.31 (s, 1H), 8.27-8.18 (m, 4H),4.26 (d, J = 7.0 Hz, 2H), 3.58 (t, J = 7.1 Hz, 2H), 3.55-3.47 (m, 1H),2.11-1.94 (m, 3H), 1.81-1.68 (m, 4H), 1.49 (td, J = 14.7, 7.3 Hz, 2H),1.33-1.15 (m, 4H), 1.02 (s, 3H); MS m/z 448.3 (M + 1). 35

UNC843A +++ ¹H NMR (400 MHz, CD₃OD) δ 9.30 (s, 1H), 8.18 (q, J = 8.7 Hz,4H), 4.26 (d, J = 7.0 Hz, 2H), 3.57 (t, J = 7.1 Hz, 2H), 3.54-3.47 (m,1H), 2.09- 1.92 (m, 6H), 1.81-1.67 (m, 4H), 1.48 (dq, J = 14.6, 7.4 Hz,2H), 1.32-1.16 (m, 4H), 1.02 (t, J = 7.4 Hz, 3H); MS m/z 501.3 (M + 1).36

UNC84A4 +++ ¹H NMR (400 MHz, CD₃OD) δ 9.23 (s, 1H), 8.08-7.93 (m, 4H),4.23 (d, J = 7.0 Hz, 2H), 3.60-3.47 (m, 3H), 2.08-1.93 (m, 3H),1.80-1.65 (m, 4H), 1.47 (td, J = 14.9, 7.4 Hz, 2H), 1.31-1.15 (m, 4H),1.00 (t, J = 7.4 Hz, 3H); MS m/z 460.2 (M + 1). 37

UNC845A +++ ¹H NMR (400 MHz, CD₃OD) δ 9.30 (s, 1H), 8.20 (d, J = 8.0 Hz,2H), 8.01 (d, J = 8.0 Hz, 2H), 4.26 (d, J = 7.0 Hz, 2H), 3.58 (t, J =7.2 Hz, 2H), 3.55-3.45 (m, 1H), 2.58 (s, 3H), 2.11-1.93 (m, 3H), 1.73(td, J = 14.9, 7.9 Hz, 4H), 1.49 (dq, J = 14.8, 7.5 Hz, 2H), 1.32-1.14(m, 4H), 1.02 (t, J = 7.7 Hz, 3H); MS m/z 473.3 (M + 1). 38

UNC784A ++ ¹H NMR (400 MHz, CDCl₃) δ 8.86 (s, 1H), 7.91-7.83 (m, 2H),7.21- 7.12 (m, 2H), 5.44 (s, 1H), 4.59 (tt, J = 11.6, 4.2 Hz, 1H), 3.51(dd, J = 12.9, 7.0 Hz, 2H), 2.17-1.88 (m, 6H), 1.80-1.71 (m, 1H),1.70-1.60 (m, 2H), 1.55- 1.41 (m, 4H), 1.34 (ddt, J = 16.4, 12.9, 6.3Hz, 1H), 0.99 (t, J = 7.3 Hz, 3H); MS m/z 368.3 (M + 1). 39

UNC785A +++ ¹H NMR (400 MHz, DMSO-d₆) δ 13.07 (bs, 1H), 9.19 (s, 1H),8.16- 7.99 (m, 4H), 7.70 (bs, 2H), 4.14 (d, J = 5.4 Hz, 2H), 3.39-3.29(m, 2H), 2.95 (bs, 1H), 1.98-1.82 (m, 3H), 1.68 (d, J = 11.6 Hz, 2H),1.62-1.51 (m, 2H), 1.36 (dt, J = 14.4, 7.3 Hz, 2H), 1.31-1.08 (m, 5H),0.92 (t, J = 7.3 Hz, 3H); MS m/z 423.3 (M + 1). 40

UNC904A ++ ¹H NMR (400 MHz, CDCl₃) δ 8.94 (s, 1H), 8.10-8.03 (m, 2H),7.99- 7.92 (m, 2H), 5.30 (bs, 1H), 4.68-4.56 (m, 1H), 4.33 (q, J = 5.4Hz, 1H), 3.52 (dd, J = 12.9, 7.0 Hz, 2H), 2.70 (d, J = 5.4 Hz, 3H),2.16-1.89 (m, 6H), 1.77 (d, J = 12.7 Hz, 1H), 1.66 (dt, J = 14.8, 7.3Hz, 2H), 1.54-1.28 (m, 5H), 0.99 (t, J = 7.3 Hz, 3H); MS m/z 443.2 (M +1). 41

UNC905A +++ ¹H NMR (400 MHz, CDCl₃) δ 8.96 (s, 1H), 8.07 (d, J = 8.5 Hz,2H), 7.97 (d, J = 8.5 Hz, 2H), 5.33 (s, 1H), 4.92-4.79 (m, 1H), 4.32(dd, J = 10.8, 5.4 Hz, 1H), 4.17 (dd, J = 11.7, 3.3 Hz, 2H), 3.64 (dd, J= 11.9, 10.2 Hz, 2H), 3.52 (dd, J = 12.9, 6.9 Hz, 2H), 2.71 (d, J = 5.4Hz, 3H), 2.48 (ddd, J = 25.0, 12.5, 4.7 Hz, 2H), 1.97 (d, J = 10.8 Hz,2H), 1.66 (dt, J = 14.8, 7.2 Hz, 2H), 1.47 (dq, J = 14.5, 7.3 Hz, 2H),0.99 (t, J = 7.3 Hz, 3H); MS m/z 445.2 (M + 1). 42

UNC906A ++++ ¹H NMR (400 MHz, CDCl₃ + CD₃OD) δ 8.78 (s, 1H), 7.92 (d, J= 8.4 Hz, 2H), 7.82 (d, J = 8.3 Hz, 2H), 4.51 (s, 1H), 3.64 (s, 1H),3.37 (t, J = 7.0 Hz, 2H), 2.50 (s, 3H), 2.17- 1.86 (m, 6H), 1.61-1.29(m, 6H), 0.87 (t, J = 7.3 Hz, 3H); MS m/z 459.2 (M + 1). 43

UNC907A ++++ ¹H NMR (400 MHz, CDCl₃ + CD₃OD) δ 8.82 (s, 1H), 7.95 (dd, J= 8.2, 6.2 Hz, 2H), 7.84 (dd, J = 8.5, 1.8 Hz, 2H), 4.66-4.48 (m, 1H),3.44-3.33 (m, 3H), 2.53 (s, 3H), 2.46- 2.32 (m, 1H), 1.99-1.81 (m, 3H),1.79 1.61 (m, 3H), 1.55 (dt, J = 14.8, 7.4 Hz, 2H), 1.36 (td, J = 14.8,7.4 Hz, 3H), 0.88 (t, J = 7.3 Hz, 3H); MS m/z 459.2 (M + 1). 44

UNC908 +++ ¹H NMR (400 MHz, CDCl₃) δ 8.95 (s, 1H), 8.10-8.03 (m, 2H),8.00- 7.93 (m, 2H), 5.37 (bs, 1H), 4.41-4.30 (m, 1H), 4.24 (d, J = 7.1Hz, 2H), 4.03-3.91 (m, 2H), 3.51 (dd, J = 13.0, 6.9 Hz, 2H), 3.38 (td, J= 11.5, 2.6 Hz, 2H), 2.71 (d, J = 5.4 Hz, 3H), 2.40 2.24 (m, 1H),1.71-1.61 (m, 2H), 1.60- 1.56 (m, 1H), 1.54-1.38 (m, 5H), 0.99 (t, J =7.3 Hz, 3H); MS m/z 459.3 (M + 1). 45

UNC909A +++ ¹H NMR (400 MHz, CDCl₃) δ 8.95 (s, 1H), 8.10-8.03 (m, 2H),7.99- 7.93 (m, 2H), 5.38 (bs, 1H), 4.47-4.33 (m, 3H), 3.95 (dd, J =11.5, 3.5 Hz, 2H), 3.49 (dd, J = 13.1, 6.8 Hz, 2H), 3.33 (td, J = 11.7,1.8 Hz, 2H), 2.71 (d, J = 5.4 Hz, 3H), 1.97-1.86 (m, 2H), 1.76 (d, J =12.7 Hz, 2H), 1.65 (dt, J = 12.7, 7.4 Hz, 2H), 1.55-1.30 (m, 5H), 0.98(t, J = 7.3 Hz, 3H); MS m/z 473.3 (M + 1). 46

UNC910A ++ ¹H NMR (400 MHz, CDCl₃) δ 8.94 (s, 1H), 8.09-8.01 (m, 2H),8.00- 7.92 (m, 2H), 5.37 (s, 1H), 4.49-4.34 (m, 3H), 3.76- 3.60 (m, 4H),3.50 (dd, J = 13.0, 6.9 Hz, 2H), 2.71 (d, J = 5.4 Hz, 3H), 2.44 (bs,4H), 2.19-2.07 (m, 2H), 1.71-1.53 (m, 4H), 1.51- 1.37 (m, 2H), 0.98 (t,J = 7.3 Hz, 3H); MS m/z 488.3 (M + 1). 47

UNC911A +++ ¹H NMR (400 MHz, CDCl₃) δ 8.79 (s, 1H), 7.92 (d, J = 8.6 Hz,2H), 7.83 (d, J = 8.6 Hz, 2H), 4.24 (t, J = 7.0 Hz, 2H), 3.45-3.30 (m,3H), 2.50 (s, 3H), 1.81 (t, J = 11.5 Hz, 3H), 1.71 (dd, J = 13.7, 6.8Hz, 2H), 1.53 (dt, J = 14.9, 7.3 Hz, 2H), 1.40-1.27 (m, 2H), 1.08 (dd, J= 23.1, 12.5 Hz, 4H), 1.00-0.89 (m, 2H), 0.86 (t, J = 7.9 Hz, 3H); MSm/z 487.3 (M + 1). 48

UNC912A +++ ¹H NMR (400 MHz, CD₃OD) δ 9.03 (s, 1H), 8.17-8.09 (m, 2H),7.99- 7.92 (m, 2H), 4.32 (t, J = 6.9 Hz, 2H), 3.48 (t, J = 7.0 Hz, 2H),3.42 (dt, J = 10.8, 4.2 Hz, 1H), 2.58 (s, 3H), 2.02-1.84 (m, 4H), 1.76(d, J = 11.6 Hz, 2H), 1.66 (dt, J = 14.8, 7.3 Hz, 2H), 1.52-1.39 (m,2H), 1.29-1.13 (m, 5H), 0.99 (t, J = 7.4 Hz, 3H), 0.96-0.86 (m, 2H); MSm/z 501.3 (M + 1). 49

UNC913A ++++ ¹H NMR (400 MHz, CD₃OD) δ 9.17 (s, 1H), 8.20-8.14 (m, 2H),8.01- 7.95 (m, 2H), 4.26 (d, J = 6.8 Hz, 2H), 3.52 (t, J = 7.1 Hz, 2H),3.13-3.00 (m, 1H), 2.81 (s, 3H), 2.15- 2.01 (m, 3H), 1.86 (d, J = 12.0Hz, 2H), 1.68 (dt, J = 12.7, 7.4 Hz, 2H), 1.48 (dt, J = 14.8, 7.3 Hz,2H), 1.41-1.21 (m, 4H), 1.00 (t, J = 7.4 Hz, 3H); MS m/z 472.3 (M + 1).50

UNC914A +++ ¹H NMR (400 MHz, CD₃OD) δ 9.13 (s, 1H), 8.17 (d, J = 8.4 Hz,2H), 7.97 (d, J = 8.5 Hz, 2H), 4.34 (d, J = 6.7 Hz, 2H), 3.50 (t, J =7.1 Hz, 2H), 3.41 (d, J = 12.8 Hz, 2H), 3.00 (td, J = 12.8, 2.7 Hz, 2H),2.58 (s, 3H), 2.46- 2.34 (m, 1H), 1.95 (d, J = 12.7 Hz, 2H), 1.74-1.53(m, 4H), 1.51-1.39 (m, 2H), 1.00 (t, J = 7.4 Hz, 3H); MS m/z 458.3 (M +1). 51

UNC958A +++ ¹H NMR (400 MHz, CD₃OD) δ 9.09 (s, 1H), 8.02-7.93 (m, 2H),7.32- 7.22 (m, 2H), 4.27 (d, J = 7.9 Hz, 2H), 3.52 (t, J = 7.1 Hz, 2H),2.24-2.09 (m, 1H), 1.88 (d, J = 15.8 Hz, 2H), 1.79-1.55 (m, 6H),1.52-1.38 (m, 4H), 1.34 (s, 3H), 1.00 (t, J = 7.4 Hz, 3H); MS m/z 411.3(M + 1). 52

UNC988A +++ ¹H NMR (400 MHz, CDCl₃) δ 8.94 (s, 1H), 8.10-8.04 (m, 2H),7.99- 7.93 (m, 2H), 5.31 (bs, 1H), 5.05 (dt, J = 13.3, 6.7 Hz, 1H), 4.35(q, J = 5.4 Hz, 1H), 3.51 (dd, J = 12.9, 7.0 Hz, 2H), 2.71 (d, J = 5.4Hz, 3+561), 1.70-1.61 (m, 2H), 1.59 (d, J = 6.7 Hz, 6H), 1.52-1.41 (m,2H), 0.99 (t, J = 7.3 Hz, 3H); MS m/z 403.0 (M + 1). 53

UNC989A ++ ¹H NMR (400 MHz, CDCl₃) δ 8.86 (s, 1H), 8.00-7.92 (m, 2H),7.91- 7.83 (m, 2H), 4.42 (t, J = 5.0 Hz, 2H), 4.01 (t, J = 5.0 Hz, 2H),3.38 (t, J = 7.1 Hz, 3H), 2.56 (s, 3H), 1.63-1.50 (m, 2H), 1.44- 1.30(m, 2H), 0.90 (t, J = 7.3 Hz, 3H); MS m/z 405.2 (M + 1). 54

UNC990 ++ ¹H NMR (400 MHz, CDCl₃) δ 8.88 (s, 1H), 7.98 (d, J = 8.6 Hz,2H), 7.90 (d, J = 8.6 Hz, 2H), 4.43 (t, J = 6.2 Hz, 2H), 3.50 (t, J =5.8 Hz, 2H), 3.40 (t, J = 7.1 Hz, 2H), 2.59 (s, 3H), 2.10-2.00 (m, 2H),1.60 (dt, J = 14.9, 7.4 Hz, 2H), 1.40 (dq, J = 14.5, 7.3 Hz, 2H), 0.92(t, J = 7.3 Hz, 3H); MS m/z 419.2 (M + 1). 55

UNC1084A ++++ ¹H NMR (400 MHz, CDCl₃ + CD₃OD) δ 8.74 (s, 1H), 7.51-7.41(m, 2H), 6.94 (t, J = 8.6 Hz, 1H), 4.04 (d, J = 6.8 Hz, 2H), 3.80-3.74(m, 4H), 3.35 (t, J = 7.0 Hz, 2H), 3.10-3.01 (m, 4H), 2.87 (dd, J =13.6, 9.7 Hz, 1H), 1.93 (d, J = 10.1 Hz, 3H), 1.70 (d, J = 12.7 Hz, 2H),1.58-1.47 (m, 2H), 1.33 (td, J = 14.6, 7.2 Hz, 2H), 1.27-1.17 (m, 2H),1.09 (dd, J = 24.2, 11.9 Hz, 2H), 0.86 (t, J = 7.3 Hz, 3H); MS m/z 482.4(M + 1). 56

UNC1085A ++++ ¹H NMR (400 MHz, CD₃OD) δ 9.25 (s, 1H), 7.90 (ddd, J =12.1, 9.3, 1.6 Hz, 2H), 7.76 (t, J = 7.7 Hz, 1H), 4.52 (s, 2H), 4.26 (d,J = 6.8 Hz, 2H), 3.98 (bs, 4H), 3.54 (t, J = 7.1 Hz, 2H), 3.40 (bs, 4H),3.07 (ddd, J = 11.6, 7.7, 4.0 Hz, 1H), 2.16-2.02 (m, 3H), 1.86 (d, J =11.7 Hz, 2H), 1.75-1.64 (m, 2H), 1.53-1.22 (m, 6H), 1.00 (t, J = 7.4 Hz,3H); MS m/z 496.3 (M + 1). 57

UNC1167A ++++ ¹H NMR (400 MHz, CD₃OD) δ 9.10 (s, 1H), 7.94 (d, J = 7.0Hz, 2H), 7.60-7.87 (m, 3H), 4.24 (d, J = 6.7 Hz, 2H), 3.52 (t, J = 7.0Hz, 2H), 3.14-2.99 (m, 1H), 2.17-1.98 (m, 3H), 1.86 (d, J = 12.6 Hz,2H), 1.75-1.60 (m, 2H), 1.55-1.20 (m, 6H), 1.01 (t, J = 7.3 Hz, 3H); MSm/z 379.3 (M + 1). 58

UNC1168A ++++ ¹H NMR (400 MHz, CD₃OD) δ 9.05 (s, 1H), 7.86 (d, J = 8.4Hz, 2H), 7.67 (d, J = 8.4 Hz, 2H), 4.21 (d, J = 6.7 Hz, 2H), 3.49 (t, J= 7.0 Hz, 2H), 3.14-3.00 (m, 1H), 2.14- 1.98 (m, 3H), 1.83 (d, J = 12.3Hz, 2H), 1.73-1.61 (m, 2H), 1.53-1.19 (m, 6H), 1.00 (t, J = 7.3 Hz, 3H);MS m/z 457.2 (M + 1). 59

UNC1306A +++ ¹H NMR (400 MHz, DMSO-d₆) δ 10.02 (s, 1H), 9.32 (s, 1H),8.01 (bs, 2H), 7.91 (dd, J = 12.8, 8.5 Hz, 4H), 7.35 (t, J = 7.9 Hz,2H), 7.14 (d, J = 8.7 Hz, 2H), 7.00 (t, J = 7.3 Hz, 1H), 4.19 (d, J =6.8 Hz, 2H), 3.81 (m, 4H), 3.29- 3.19 (m, 4H), 2.94 (bs, 1H), 2.06-1.89(m, 3H), 1.71 (d, J = 11.0 Hz, 2H), 1.38-1.24 (m, 2H), 1.24- 1.09 (m,2H); MS m/z 484.3 (M + 1). 60

UNC1307A +++ ¹H NMR (400 MHz, DMSO-d₆) δ 10.01 (s, 1H), 9.31 (s, 1H),7.97 (bs, 2H), 7.92 (d, J = 8.8 Hz, 2H), 7.79 (t, J = 2.1 Hz, 1H), 7.36(d, J = 9.3 Hz, 1H), 7.22 (t, J = 8.1 Hz, 1H), 7.12 (d, J = 8.8 Hz, 2H),6.58 (dd, J = 8.1, 2.3 Hz, 1H), 4.19 (d, J = 6.8 Hz, 2H), 3.81-3.77 (m,7H), 3.28-3.18 (m, 4H), 2.93 (bs, 1H), 2.07-1.88 (m, 3H), 1.70 (d, J =11.2 Hz, 2H), 1.29 (dd, J = 24.0, 11.7 Hz, 2H), 1.18 (dd, J = 24.0, 12.2Hz, 2H); MS m/z 514.3 (M + 1). 61

UNC1308A +++ ¹H NMR (400 MHz, DMSO-d₆) δ 9.84 (s, 1H), 9.26 (s, 1H),7.95 (bs, 2H), 7.90 (d, J = 8.6 Hz, 2H), 7.77 (d, J = 8.8 Hz, 2H), 7.11(d, J = 8.7 Hz, 2H), 6.94 (d, J = 9.0 Hz, 2H), 4.16 (d, J = 6.5 Hz, 2H),3.83-3.77 (m, 4H), 3.75 (s, 3H), 3.27-3.17 (m, 4H), 2.96 (s, 1H), 1.95(d, J = 9.3 Hz, 3H), 1.71 (d, J = 11.7 Hz, 2H), 1.30 (dd, J = 24.4, 11.8Hz, 2H), 1.17 (dd, J = 25.2, 12.5 Hz, 2H); MS m/z 514.3 (M + 1).

Example 71-(4-Hydroxy-cyclohexyl)-3-(4-piperidinsulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-6-amineGeneral Procedure E:

1-(4-hydroxy-cyclohexyl)-3-bromo-N-butyl-1H-pyrazolo[3,4-d]pyrimidin-6-amine

To a solution of 3-bromo-N-butyl-1H-pyrazolo[3,4-d]pyrimidin-6-amine(122 mg, 0.45 mmol) and 4-hydroxy-cyclohexyl chloride (260 mg, 1.9 mmol)in DMF (6.0 mL) was added K₂CO₃ (270 g, 2.0 mmol). The mixture washeated at 150° C. for overnight. After the reaction was cooled to roomtemperature, the reaction was quenched with H₂O. The reaction mixturewas partitioned in H₂O and EtOAc. The aqueous phase was extracted withEtOAc (3×). The combined organic phase were dried (Na₂SO₄) andconcentrated. The residue was purified by Isco to provide a mixture ofcis- andtrans-1-(4-hydroxy-cyclohexyl)-3-bromo-N-butyl-1H-pyrazolo[3,4-d]pyrimidin-6-amine(90 mg, 54%) as a yellow solid.

1-(4-hydroxy-cyclohexyl)-3-(4-piperidinsulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine

A 10 mL microwave tube was charged with1-(4-hydroxy-cyclohexyl)-3-bromo-N-butyl-1H-pyrazolo[3,4-d]pyrimidin-6-amine(0.070 g, 0.19 mmol), (4-piperidinsulfonyl) phenyl boronic acid (0.10 g,0.40 mmol), potassium carbonate (0.086 g, 0.62 mmol),tetrakis(triphenylphosphine)palladium (0.025 g, 0.022 mmol), DMF (2.0mL) and water (0.50 mL). After stirring for 5 min, the reaction was heatat 150° C. for 10 min in microwave. The reaction was diluted with EtOAcand washed with water. The aqueous layer was extracted with EtOAc (3×).The combined organic layers were dried (Na₂SO₄), concentrated, andpurified by Isco and HPLC to providecis-1-(4-hydroxy-cyclohexyl)-3-(4-piperidinsulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin)-6-amine(UNC1065A) (0.011 g, 12%) as a white solid, ¹H NMR (400 MHz, CD₃OD). δ9.21 (s, 1H), 8.22 (d, J=8.4 Hz, 2H), 7.98 (d, J=8.4 Hz, 2H), 4.79-4.69(m, 1H), 4.08-4.02 (m, 1H), 3.55 (t, J=7.1 Hz, 2H), 3.32-3.25 (m, 4H),2.62-2.46 (m, 2H), 2.07-1.96 (m, 2H), 1.89-1.65 (m, 1011), 1.48 (qd,J=14.5, 7.3 Hz, 2H), 1.01 (t, J=7.4 Hz, 3H); MS m/z 499.0 [M+1]⁺, andtrans-1-(4-hydroxy-cyclohexyl)-3-(4-piperidinsulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine(UNC1064A) (0.009 g, 10%) as a white solid. ¹H NMR (400 MHz, CD₃OD). δ9.20 (s, 1H), 8.20 (d, J=8.5 Hz, 2H), 7.98 (d, J=8.5 Hz, 2H), 4.75-4.64(m, 1H), 3.78-3.67 (m, 1H), 3.55 (t, J=7.1 Hz, 2H), 3.32-3.23 (m, 4H),2.30-2.02 (m, 6H), 1.85-1.64 (m, 6H), 1.62-1.42 (m, 4H), 1.02 (t, J=7.4Hz, 3H); MS m/z 499.0 [M+1]⁺.

Table 6 describes compounds prepared following procedures described inExample 7 (General Procedure E), using appropriate reagents.

TABLE 6 Physical Data Mer MS m/z (M + 1) or/and Structure Compound_IDIC₅₀ ¹H NMR (400 MHz)  1

UNC1060A +++ ¹H NMR (400 MHz, CD₃OD) δ 9.07 (s, 1H), 8.04-7.96 (m, 2H),7.30- 7.22 (m, 2H), 4.75-4.64 (m, 1H), 4.07-4.02 (m, 1H), 3.53 (t, J =7.1 Hz, 2H), 2.60-2.46 (m, 2H), 2.06-1.96 (m, 2H), 1.86- 1.73 (m, 4H),1.73-1.64 (m, 2H), 1.47 (dq, J = 14.5, 7.3 Hz, 2H), 1.01 (t, J = 7.4 Hz,3H); MS m/z 384.2 (M + 1).  2

UNC1040A ++ ¹H NMR (400 MHz, CD₃OD). δ 8.87 (s, 1H), 7.67-7.59 (m, 2H),7.55- 7.45 (m, 2H), 4.28 (d, J = 6.9 Hz, 2H), 3.13-3.03 (m, 1H), 3.08(s, 3H), 2.16- 2.03 (m, 3H), 1.92-1.81 (m, 2H), 1.48-1.23 (m, 4H); MSm/z 371.2 (M + 1).  3

UNC1058A ++++ ¹H NMR (400 MHz, CD₃OD). δ 9.20 (s, 1H), 8.14 (d, J = 8.4Hz, 2H), 8.05 (d, J = 8.4 Hz, 2H), 4.27 (d, J = 6.8 Hz, 2H), 3.53 (t, J= 7.1 Hz, 2H), 3.13-3.02 (m, 1H), 2.16- 2.02 (m, 3H), 1.92-1.82 (m, 2H),1.69 (dt, J = 14.8, 7.3 Hz, 2H), 1.54-1.22 (m, 6H), 1.01 (t, J = 7.4 Hz,3H); MS m/z 437.3 (M + 1).  4

UNC1062A ++++ ¹H NMR (400 MHz, CD₃OD). δ 9.20 (s, 1H), 8.26-8.20 (m,2H), 7.95- 7.89 (m, 2H), 4.75-4.64 (m, 1H), 3.79-3.68 (m, 1H), 3.73 (dd,J = 10.2, 5.7 Hz, 4H), 3.55 (t, J = 7.1 Hz, 2H), 3.08-2.97 (m, 4H),2.36-2.01 (m, 6H), 1.76-1.65 (m, 2H), 1.62- 1.42 (m, 4H), 1.02 (t, J =7.4 Hz, 3H); MS m/z 515.0 (M + 1).  5

UNC1063A ++++ ¹H NMR (400 MHz, CD₃OD). δ 9.19 (s, 1H), 8.28-8.20 (m,2H), 7.96- 7.88 (m, 2H), 4.78-4.69 (m, 1H), 4.08-4.02 (m, 1H), 3.78-3.67(m, 4H), 3.54 (t, J = 7.1 Hz, 2H), 3.08-2.98 (m, 4H), 2.62- 2.46 (m,2H), 2.07-1.96 (m, 2H), 1.90-1.62 (m, 6H), 1.48 (dq, J = 14.5, 7.3 Hz,2H), 1.01 (t, J = 7.4 Hz, 3H); MS m/z 515.2 (M + 1).  6

UNC1066A ++++ ¹H NMR (400 MHz, CD₃OD). δ 9.11 (s, 1H), 8.17 (d, J = 8.6Hz, 2H), 8.00 (d, J = 8.6 Hz, 2H), 4.73-4.63 (m, 1H), 3.79- 3.67 (m,1H), 3.51 (t, J = 7.1 Hz, 2H), 2.30-2.01 (m, 7H), 1.69 (td, J = 14.7,7.4 Hz, 2H), 1.61-1.42 (m, 4H), 1.01 (t, J = 7.4 Hz, 3H), 0.62-0.47 (m,4H); MS m/z 485.0 (M + 1).  7

UNC1003A +++ ¹H NMR (400 MHz, CD₃OD). δ 9.06 (s, 1H), 7.83 (d, J = 8.9Hz, 2H), 7.08 (d, J = 8.8 Hz, 2H), 4.68-4.58 (m, 1H), 3.89- 3.81 (m,4H), 3.76-3.67 (m, 1H), 3.55 (t, J = 7.1 Hz, 2H), 3.30-3.21 (m, 4H),2.00 (m, 6H), 1.76-1.66 (m, 2H), 1.59- 1.43 (m, 4H), 1.02 (t, J = 7.4Hz, 3H); MS m/z 451.35 (M + 1).  8

UNC1170A ++++ ¹H NMR (400 MHz, CD₃OD). δ 9.22 (s, 1H), 8.07 (d, J = 8.4Hz, 2H), 7.60 (d, J = 8.4 Hz, 2H), 4.26 (d, J = 6.8 Hz, 2H), 3.85-3.59(m, 8H), 3.55 (t, J = 7.1 Hz, 2H), 3.13- 3.02 (m, 1H), 2.15-2.01 (m,3H), 1.87 (d, J = 12.1 Hz, 2H), 1.75-1.65 (m, 2H), 1.54-1.22 (m, 6H),1.01 (t, J = 7.4 Hz, 3H); MS m/z 492.4 (M + 1).  9

UNC1179A ++++ ¹H NMR (400 MHz, CD₃OD) δ 9.13 (s, 1H), 8.05 (d, J = 8.5Hz, 2H), 7.96 (d, J = 8.7 Hz, 2H), 4.25 (d, J = 6.8 Hz, 2H), 3.51 (t, J= 7.1 Hz, 2H), 3.12-3.02 (m, 1H), 2.95 (s, 3H), 2.15-2.01 (m, 3H), 1.85(d, J = 12.3 Hz, 2H), 1.74-1.62 (m, 2H), 1.53-1.21 (m, 6H), 1.00 (t, J =7.4 Hz, 3H); MS m/z 436.3 (M + 1). 10

UNC1171A ++++ ¹H NMR (400 MHz, CD₃OD) δ 9.17 (s, 1H), 8.05 (d, J = 8.2Hz, 2H), 7.68 (d, J = 8.2 Hz, 2H), 4.25 (d, J = 6.8 Hz, 2H), 3.62 (t, J= 8.0 Hz, 2H), 3.57-3.47 (m, 4H), 3.13- 3.02 (m, 1H), 2.14-1.81 (m, 9H),1.75-1.64 (m, 2H), 1.53-1.20 (m, 6H), 1.01 (t, J = 7.4 Hz, 3H); MS m/z476.4 (M + 1). 11

UNC1180A ++++ ¹H NMR (400 MHz, CD₃OD) δ 9.13 (s, 1H), 8.05 (d, J = 8.0Hz, 2H), 7.58 (d, J = 8.0 Hz, 2H), 4.72-4.60 (m, 1H), 3.86- 3.44 (m,11H), 2.29-1.99 (m, 6H), 1.76-1.64 (m, 2H), 1.61-1.41 (m, 4H), 1.02 (t,J = 7.3 Hz, 3H); MS m/z 479.3 (M + 1). 12

UNC1172A ++++ ¹H NMR (400 MHz, CD₃OD) δ 9.09 (s, 1H), 8.04 (d, J = 8.0Hz, 2H), 7.56 (d, J = 6.5 Hz, 2H), 4.72-4.62 (m, 1H), 4.08- 4.02 (m,1H), 3.89-3.58 (m, 6H), 3.53 (t, J = 6.4 Hz, 2H), 3.58-3.43 (m, 2H),2.60-2.45 (m, 2H), 2.07-1.95 (m, 2H), 1.89- 1.61 (m, 6H), 1.52-1.39 (m,2H), 0.99 (t, J = 7.3 Hz, 3H); MS m/z 479.3 (M + 1). 13

UNC1173A ++++ ¹H NMR (400 MHz, CD₃OD) δ 9.08 (s, 1H), 8.03 (d, J = 7.9Hz, 2H), 7.65 (d, J = 7.9 Hz, 2H), 4.74-4.63 (m, 1H), 4.08- 4.02 (m,1H), 3.63 (t, J = 6.8 Hz, 2H), 3.56-3.47 (m, 4H), 2.61-2.45 (m, 2H),2.07-1.89 (m, 6H), 1.88-1.62 (m, 6H), 1.53- 1.40 (m, 2H), 0.99 (t, J =7.3 Hz, 3H); MS m/z 463.3 (M + 1). 14

UNC1181A ++++ ¹H NMR (400 MHz, CD₃OD) δ 9.12 (s, 1H), 7.94 (d, J = 8.4Hz, 2H), 7.80 (d, J = 8.4 Hz, 2H), 4.21 (d, J = 6.4 Hz, 2H), 3.97 (t, J= 6.9 Hz, 2H), 3.51 (t, J = 6.9 Hz, 2H), 3.13-3.01 (m, 1H), 2.63 (t, J =8.0 Hz, 2H), 2.27- 2.15 (m, 2H), 2.13-2.00 (m, 3H), 1.85 (d, J = 11.9Hz, 2H), 1.74-1.62 (m, 2H), 1.54-1.20 (m, 6H), 1.00 (t, J = 7.3 Hz, 3H);MS m/z 462.3 (M + 1). 15

UNC1182A ++++ ¹H NMR (400 MHz, CD₃OD) δ 9.16 (s, 1H), 8.05-7.99 (m, 2H),7.60- 7.54 (m, 2H), 4.32 (s, 2H), 4.23 (d, J = 6.8 Hz, 2H), 4.10-4.04(m, 2H), 3.85 (dd, J = 5.8, 4.3 Hz, 2H), 3.53 (t, J = 7.1 Hz, 2H),3.13-3.01 (m, 1H), 2.13- 2.01 (m, 3H), 1.86 (d, J = 11.6 Hz, 2H),1.74-1.65 (m, 2H), 1.53-1.21 (m, 6H), 1.01 (t, J = 7.4 Hz, 3H); MS m/z478.3 (M + 1). 16

UNC1183A ++++ ¹H NMR (400 MHz, CD₃OD) δ 9.11 (s, 1H), 8.03 (d, J = 8.1Hz, 2H), 7.68 (d, J = 8.1 Hz, 2H), 4.72-4.61 (m, 1H), 3.78- 3.68 (m,1H), 3.63 (t, J = 6.8 Hz, 2H), 3.56-3.47 (m, 4H), 2.29-1.88 (m, 10H),1.75-1.63 (m, 2H), 1.61-1.41 (m, 4H), 1.01 (t, J = 7.3 Hz, 3H); MS m/z463.3 (M + 1). 17

UNC1095A ++++ ¹H NMR (400 MHz, CDCl₃) δ 9.43 (s, 1H), 8.86 (s, 1H), 7.98(s, 4H), 4.66- 4.63 (m, 1H), 4.02-3.98 (m, 4H), 3.87-3.82 (m, 1H),3.59-3.53 (m, 4H), 3.25 (t, J = 6.97 Hz, 2H), 3.12-3.09 (m, 2H), 2.93-2.82 (m, 2H), 2.22-2.16 (m, 4H), 2.11-2.08 (m, 4H), 1.72 (td, J = 7.41,14.83 Hz, 2H), 1.69-1.57 (m, 2H), 1.47 (dq, J = 7.29, 14.59 Hz, 2H),1.00 (t, J = 7.35 Hz, 3H); MS m/z 572.35 (M + 1). 18

UNC1096A ++++ ¹H NMR (400 MHz, CDCl₃) δ 9.41 (s, 1H), 8.94 (s, 1H),7.96-7.91 (m, 4H), 6.86 (s, 1H), 4.70-4.64 (m, 1H), 4.17 (s, 1H), 3.98-3.87 (m, 4H), 3.54 (s, 4H), 3.22 (t, J = 6.67 Hz, 2H), 3.07 (s, 2H),2.95-2.82 (m, 2H), 2.53-2.47 (m, 1H), 2.37-2.30 (m, 1H), 2.16- 1.98 (m,6H), 1.87-1.80 (m, 2H), 1.70 (dd, J = 7.38, 14.60 Hz, 2H), 1.46 (dq, J =7.35, 14.60 Hz, 2H), 0.99 (t, J = 7.35 Hz, 3H); MS m/z 572.30 (M + 1).19

UNC1120A ++++ ¹H NMR (400 MHz, CD₃OD) δ 8.80 (s, 1H), 7.91 (s, 4H),7.18-7.13 (m, 2H), 6.73-6.66 (m, 2H), 4.66-4.59 (m, 1H), 3.75- 3.68 (m,1H), 3.58 (d, J = 7.92 Hz, 1H), 3.49 (t, J = 7.08 Hz, 2H), 2.22-2.12 (m,4H), 2.02 (d, J = 11.21 Hz, 2H), 1.97-1.90 (m, 1H), 1.71-1.64 (m, 2H),1.51-1.42 (m, 5H), 1.05- 0.99 (m, 6H), 0.95 (d, J = 6.74 Hz, 3H); MS m/z638.30 (M + 1). 20

UNC1124A +++ ¹H NMR (400 MHz, CD₃OD) δ 9.63 (s, 1H), 8.85 (s, 1H),7.98-7.92 (m, 4H), 7.18-7.14 (m, 2H), 6.72-6.68 (m, 2H), 4.73- 4.66 (m,1H), 4.05 (s, 1H), 3.58 (d, J = 7.92 Hz, 1H), 3.51 (t, J = 7.07 Hz, 2H),2.56-2.46 (m, 2H), 2.04- 1.91 (m, 3H), 1.82-1.75 (m, 4H), 1.68 (dt, J =7.37, 14.73 Hz, 2H), 1.48 (dq, J = 7.31, 14.44 Hz, 2H), 1.05 (d, J =6.72 Hz, 3H), 1.01 (t, J = 7.35 Hz, 3H), 0.96 (d, J = 6.72 Hz, 3H); MSm/z 638.30 (M + 1). 21

UNC1125A ++++ ¹H NMR (400 MHz, CD₃OD) δ 8.96 (s, 1H), 8.06 (d, J = 8.46Hz, 2H), 7.89 (d, J = 8.54 Hz, 2H), 7.12-7.08 (m, 2H), 6.93- 6.89 (m,2H), 4.46-4.44 (m, 1H), 3.73-3.71 (m, 1H), 3.47 (t, J = 7.02 Hz, 2H),3.12 (t, J = 7.38 Hz, 2H), 2.73 (t, J = 7.43 Hz, 2H), 2.22-2.02 (m, 7H),1.69-1.62 (m, 2H), 1.54- 1.43 (m, 4H), 0.99 (t, J = 7.36 Hz, 3H); MS m/z567.20 (M + 1). 22

UNC1137A +++ ¹H NMR (400 MHz, CD₃OD) δ 9.17 (s, 1H), 8.95 (s, 1H), 8.06(d, J = 8.54 Hz, 2H), 7.96 (d, J = 8.33 Hz, 2H), 7.34-7.31 (m, 2H),6.90-6.86 (m, 2H), 4.68-4.62 (m, 1H), 3.75-3.70 (m, 1H), 3.50 (t, J =7.90 Hz, 2H), 2.24- 2.13 (m, 4H), 2.06-2.03 (m, 2H), 1.71-1.64 (m, 2H),1.58-1.38 (m, 6H), 1.10 (dd, J = 4.67, 7.89 Hz, 2H), 1.00 (t, J = 7.36Hz, 3H); MS m/z 622.30 (M + 1). 23

UNC1138A +++ ¹H NMR (400 MHz, CDCl₃) δ 9.40 (s, 1H), 8.81 (s, 1H), 8.61(s, 1H), 7.83 (d, J = 8.52 Hz, 2H), 7.67 (d, J = 8.52 Hz, 2H), 7.49-7.45 (m, 2H), 7.06 (t, J = 8.60 Hz, 2H), 4.62-4.60 (m, 1H), 3.84-3.82(m, 1H), 3.54-3.49 (m, 2H), 2.27-2.17 (m, 4H), 2.06- 2.00 (m, 2H),1.74-1.66 (m, 8H), 1.58-1.55 (m, 2H), 1.46 (dd, J = 7.38, 14.93 Hz, 2H),0.99 (t, J = 7.33 Hz, 3H); MS m/z 586.30 (M + 1). 24

UNC1174A ++++ ¹H NMR (400 MHz, CDCl₃ + CD₃OD) δ 8.78 (s, 1H), 7.90 (d, J= 8.44 Hz, 2H), 7.80 (d, J = 7.34 Hz, 2H), 4.46-4.43 (m, 1H), 3.91 (d, J= 12.95 Hz, 2H), 3.63-3.61 (m, 1H), 2.36 (t, J = 7.08 Hz, 2H), 3.22 (dt,J = 1.61, 3.24 Hz, 3H), 2.65 (d, J = 6.62 Hz, 2H), 2.54-2.51 (m, 2H),2.08- 2.00 (m, 4H), 1.93-1.90 (m, 2H), 1.58-1.46 (m, 4H), 1.31 (s, 12H),0.97- 0.91 (m, 2H), 0.89 (t, J = 7.35 Hz, 3H); MS m/z 642.40 (M + 1). 25

UNC1175A ++++ ¹H NMR (400 MHz, CDCl₃ + CD₃OD) δ 8.25 (s, 1H), 7.23 (d, J= 8.45 Hz, 2H), 7.14 (d, J = 8.20 Hz, 2H), 3.85-3.80 (m, 1H), 2.96-2.91(m, 1H), 2.72 (t, J = 7.15 Hz, 2H), 2.54- 2.52 (m, 3H), 2.07-1.99 (m,4H), 1.41-1.32 (m, 4H), 1.26-1.23 (m, 2H), 1.12 (d, J = 13.63 Hz, 2H),0.98-0.94 (m, 1H), 0.91- 0.84 (m, 2H), 0.79-0.75 (m, 2H), 0.67-0.56 (m,4H), 0.17 (t, J = 7.35 Hz, 3H); MS m/z 542.30 (M + 1). 26

UNC 1176A ++++ ¹H NMR (400 MHz, CD₃OD) δ 9.20 (brs, 1H), 9.06 (s, 1H),8.82 (brs, 1H), 7.96 (d, J = 7.39 Hz, 2H), 7.90 (d, J = 7.40 Hz, 2H),4.68-4.63 (m, 1H), 4.15 (s, 1H), 3.54-3.49 (m, 2H), 3.41-3.39 (m, 2H),2.85-2.83 (m, 5H), 2.47- 2.44 (m, 2H), 2.01-1.97 (m, 2H), 1.75-1.65 (m,8H), 1.51-1.39 (m, 4H), 0.95 (t, J = 7.35 Hz, 3H); MS m/z 542.30 (M +1). 27

UNC1177A ++++ ¹H NMR (400 MHz, CDCl₃ + CD₃OD) δ 8.81 (s, 1H), 7.95 (d, J= 8.33 Hz, 2H), 7.74 (d, J = 8.34 Hz, 2H), 4.54-4.52 (m, 1H), 3.69-3.64(m, 1H), 3.57- 3.54 (m, 2H), 3.39 (t, J = 7.07 Hz, 2H), 3.27-3.25 (m,4H), 2.44 (t, J = 10.08 Hz, 2H), 2.17-2.04 (m, 4H), 1.96-1.88 (m, 4H),1.77-1.68 (m, 2H), 1.59- 1.52 (m, 2H), 1.49-1.43 (m, 2H), 1.40-1.31 (m,2H), 0.89 (t, J = 7.35 Hz, 3H); MS m/z 557.20 (M + 1). 28

UNC1178A ++++ ¹H NMR (400 MHz, CDCl₃ + CD₃OD) δ 8.90 (s, 1H), 8.18 (d, J= 8.18 Hz, 2H), 7.86 (d, J = 7.74 Hz, 2H), 4.68-4.62 (m, 1H), 3.88-3.81(in, 1H), 3.68- 3.66 (m, 5H), 3.55-3.49 (m, 2H), 2.58-2.55 (m, 2H),2.31-2.20 (m, 6H), 2.09-2.06 (m, 2H), 1.99 (dd, J = 3.38, 14.62 Hz, 2H),1.89-1.79 (m, 2H), 1.71-1.56 (m, 4H), 1.46 (dt, J = 7.30, 14.60 Hz, 2H),1.00 (t, J = 7.35 Hz, 3H); MS m/z 571.20 (M + 1). 29

UNC1184A ++++ ¹H NMR (400 MHz, DMSO-d⁶) δ 12.68 (s, 1H), 9.18 (s, 1H),8.15 (d, J = 8.17 Hz, 2H), 7.88 (d, J = 8.22 Hz, 2H), 7.62 (s, 1H),4.55-4.49 (m, 1H), 3.62 (d, J = 6.01 Hz, 2H), 3.58- 3.51 (m, 2H), 3.17(s, 1H), 2.07-1.97 (m, 6H), 1.57 (s, 2H), 1.40-1.38 (m, 4H), 0.93 (t, J= 6.50 Hz, 3H); MS m/z 503.30 (M + 1). 30

UNC1185A ++++ ¹H NMR (400 MHz, CDCl₃) δ 8.79 (s, 1H), 7.91 (d, J = 8.34Hz, 2H), 7.80 (d, J = 8.36 Hz, 2H), 4.52- 4.46 (m, 1H), 3.91 (dd, J =6.77, 14.84 Hz, 1H), 3.64- 3.59 (m, 1H), 3.36 (s, 4H), 3.20 (s, 2H),2.10-2.00 (m, 4H), 1.91 (d, J = 10.90 Hz, 2H), 1.74 (dt, J = 6.07, 12.39Hz, 2H), 1.56-1.50 (m, 4H), 1.46-1.39 (m, 4H), 1.33 (dt, J = 7.19, 14.73Hz, 2H), 1.26-1.20 (m, 2H), 0.85 (t, J = 7.35 Hz, 3H); MS m/z 570.30(M + 1). 31

UNC1186A ++++ ¹H NMR (400 MHz, CDCl₃ + CD₃OD) δ 8.76 (s, 1H), 7.91 (d, J= 8.12 Hz, 2H), 7.80 (d, J = 8.12 Hz, 2H), 4.51-4.46 (m, 1H), 3.63-3.58(m, 2H), 3.20 (s, 4H), 3.08 (dd, J = 7.09, 14.30 Hz, 2H), 2.06-2.01 (m,4H), 1.90 (d, J = 11.10 Hz, 2H), 1.51-1.49 (m, 2H), 1.41-1.29 (m, 4H),0.96 (t, J = 7.12 Hz, 3H), 0.84 (t, J = 7.24 Hz, 3H); MS m/z 530.30 (M +1). 32

UNC1187A ++++ ¹H NMR (400 MHz, CDCl₃) δ 8.72 (s, 1H), 7.81-7.79 (m, 2H),7.69- 7.66 (m, 2H), 6.68-6.63 (m, 4H), 4.49-4.44 (m, 1H), 3.64-3.57 (m,1H), 3.39-3.32 (m, 2H), 3.21 (dt, J = 1.62, 3.25 Hz, 3H), 2.10 (s, 3H),2.04-1.98 (m, 4H), 1.90-1.87 (m, 2H), 1.51 (dt, J = 7.36, 14.80 Hz, 2H),1.43-1.37 (m, 2H), 1.31 (dd, J = 7.43, 14.98 Hz, 2H), 0.84 (t, J = 7.35Hz, 3H) ); MS m/z 535.30 (M + 1). 33

UNC1188A ++++ ¹H NMR (400 MHz, CDCl₃) δ 9.06 (s, 1H), 7.84 (d, J = 8.55Hz, 2H), 7.61 (d, J = 8.57 Hz, 2H), 4.66- 4.60 (m, 1H), 3.76-3.70 (m,1H), 3.55-3.48 (m, 6H), 2.30-2.10 (m, 4H), 2.10-1.92 (m, 6H), 1.77- 1.63(m, 2H), 1.61-1.40 (m, 4H), 1.02 (t, J = 7.32 Hz, 3H); MS m/z 478.30(M + 1). 34

UNC1189A +++ ¹H NMR (400 MHz, CDCl₃ + CD₃OD) δ 8.84 (s, 1H), 7.71 (d, J= 8.53 Hz, 2H), 7.51 (d, J = 8.48 Hz, 2H), 4.59-4.51 (m, 1H), 4.02 (s,1H), 3.32 (s, 1H), 2.88-2.82 (m, 9H), 2.51- 2.33 (m, 2H), 1.99-1.90 (m,6H), 1.77-1.58 (m, 6H), 1.43-1.35 (m, 2H), 0.91 (t, J = 7.3 Hz, 3H); MSm/z 478.30 (M + 1). 35

UNC1190A ++++ ¹H NMR (400 MHz, CDCl₃ + CD₃OD) δ 8.81 (s, 1H), 7.71 (d, J= 8.41 Hz, 2H), 7.49 (d, J = 8.29 Hz, 2H), 4.54 (s, 1H), 3.75- 3.67 (m,4H), 2.24 (s, 9H), 2.15-2.12 (m, 4H), 2.00- 1.98 (m, 2H), 1.70-1.58 (m,2H), 1.54-1.49 (m, 2H), 1.46-1.38 (m, 2H), 0.94 (t, J = 7.35 Hz, 3H); MSm/z 494.30 (M + 1). 36

UNC1191A +++ ¹H NMR (400 MHz, CDCl₃ + CD₃OD) δ 8.80 (s, 1H), 7.73 (d, J= 8.53 Hz, 2H), 7.48 (d, J = 8.53 Hz, 2H), 4.62-4.54 (m, 1H), 4.07 (s,1H), 3.76-3.68 (m, 4H), 3.50-3.45 (m, 5H), 2.54-2.38 (m, 2H), 1.98 (d, J= 12.93 Hz, 2H), 1.90-1.70 (m, 8H), 1.64 (dt, J = 7.31, 14.58, 2H), 1.41(dd, J = 7.41, 14.83 Hz, 2H), 0.94 (t, J = 7.32 Hz, 3H); MS m/z 494.30(M + 1). 37

UNC1192 ++++ ¹H NMR (400 MHz, CDCl₃ + CD₃OD) δ 8.81 (s, 1H), 7.67 (d, J= 8.51 Hz, 2H), 7.47 (d, J = 8.49 Hz, 2H), 4.57-4.51 (m, 1H), 3.76-3.71(m, 1H), 3.48 (t, J = 7.15 Hz, 2H), 3.16 (t, J = 7.02 Hz, 2H), 2.76 (s,4H), 2.19-2.13 (m, 4H), 2.01-1.98 (m, 2H), 1.71- 1.59 (m, 2H), 1.56-1.39(m, 6H), 0.93 (dt, J = 7.35, 14.83 Hz, 6H); MS m/z 466.30 (M + 1). 38

UNC1193A +++ ¹H NMR (400 MHz, CDCl₃ + CD₃OD) δ 8.72 (s, 1H), 7.61 (d, J= 8.48 Hz, 2H), 7.41 (d, J = 8.51 Hz, 2H), 4.58-4.52 (m, 1H), 4.07 (s,1H), 3.46 (t, J = 7.15 Hz, 2H), 3.17 (t, J = 7.02 Hz, 2H), 2.53-2.39 (m,2H), 2.00 (s, 4H), 1.83-1.58 (m, 6H), 1.54- 1.51 (m, 2H), 1.43-1.37 (m,2H), 0.92 (dt, J = 7.39, 9.95 Hz, 6H); MS m/z 466.30 (M + 1). 39

UNC1222A ++++ ¹H NMR(400 MHz, CDCl₃) δ 9.46 (s, 1H), 8.60 (s, 1H), 7.67(d, J = 8.57 Hz, 2H), 7.47 (d, J = 8.60 Hz, 2H), 6.76 (s, 1H), 4.59-4.53(m, 1H), 4.15- 4.07 (m, 1H), 3.84-3.75 (m, 1H), 3.53-3.48 (m, 2H),2.17-2.12 (m, 4H), 2.03-1.98 (m, 4H), 1.77- 1.49 (m, 8H), 1.48-1.39 (m,4H), 0.97 (t, J = 7.35 Hz, 3H); MS m/z 492.30 (M + 1). 40

UNC1223A +++ ¹H NMR (400 MHz, CDCl₃) δ 8.72 (s, 1H), 7.74 (d, J = 8.52Hz, 2H), 7.41 (d, J = 8.62 Hz, 2H), 6.43 (s, 1H), 4.68 (d, J = 6.47 Hz,1H), 4.62-4.56 (m, 1H), 4.16-4.07 (m, 2H), 3.54-3.49 (m, 2H), 2.57- 2.42(m, 2H), 2.04-1.96 (m, 4H), 1.84-1.71 (m, 5H), 1.70-1.57 (m, 5H),1.49-1.36 (m, 4H), 0.96 (t, J = 7.35 Hz, 3H); MS m/z 492.30 (M + 1). 41

UNC1142A ++++ ¹H NMR (400 MHz, CDCl₃) δ 8.920 (s, 1H), 8.08-8.00 (m,2H), 7.89- 7.81 (m, 2H), 5.32 (bs, 1H), 4.72-4.56 (m, 1H), 3.91-3.76 (m,1H), 3.52 (dd, J = 12.9, 6.9 Hz, 2H), 3.09 (bs, 4H), 2.53 (bs, 4H), 2.41(q, J = 7.2 Hz, 2H), 2.30-2.14 (m, 4H), 2.13-1.99 (m, 2H), 1.66 (dt, J =14.7, 7.3 Hz, 2H), 1.59-1.52 (m, 3H), 1.47 (dq, J = 14.4, 7.3 Hz, 2H),1.03 (t, J = 7.1 Hz, 3H), 1.00 (t, J = 7.3 Hz, 3H); MS m/z 542.3 (M +1). 42

UNC1143A ++++ ¹H NMR (400 MHz, CDCl₃) δ 8.94 (s, 1H), 8.03 (d, J = 8.3Hz, 2H), 7.88 (d, J = 8.2 Hz, 2H), 5.32 (bs, 1H), 4.73-4.56 (m, 1H),3.84 (bs, 1H), 3.52 (dd, J = 13.0, 6.6 Hz, 2H), 3.42 (bs, 4H), 2.70 (d,J = 19.2 Hz, 4H), 2.55 (bs, 2H), 2.31-2.14 (m, 4H), 2.07 (d, J = 11.0Hz, 2H), 1.86 (s, 2H), 1.70-1.63 (m, 2H), 1.63-1.55 (m, 3H), 1.51-1.39(m, 2H), 1.13- 0.94 (m, 6H); MS m/z 556.4 (M + 1). 43

UNC1144A ++++ ¹H NMR (400 MHz, CDCl₃) δ 8.94 (s, 1H), 8.05 (d, J = 8.3Hz, 2H), 7.85 (d, J = 8.3 Hz, 2H), 5.32 (s, 1H), 4.72-4.57 (m, 1H),3.96-3.77 (m, 3H), 3.52 (dd, J = 13.0, 6.8 Hz, 2H), 2.45 (s, 4H), 2.29(t, J = 11.0 Hz, 3H), 2.19 (dd, J = 18.1, 7.2 Hz, 4H), 2.07 (d, J = 11.0Hz, 2H), 1.85 (d, J = 11.2 Hz, 2H), 1.67 (dt, J = 22.3, 7.5 Hz, 5H),1.57 (d, J = 7.3 Hz, 6H), 1.51-1.37 (m, 4H), 0.99 (t, J = 7.3 Hz, 3H);MS m/z 596.4 (M + 1). 44

UNC1145A ++++ ¹H NMR (400 MHz, CDCl₃) δ 8.94 (s, 1H), 8.05 (d, J = 8.2Hz, 2H), 7.85 (d, J = 8.2 Hz, 2H), 5.32 (bs, 1H), 4.76-4.57 (m, 1H),3.85 (d, J = 10.8 Hz, 3H), 3.68 (bs, 4H), 3.52 (dd, J = 12.8, 6.6 Hz,2H), 2.48 (s, 4H), 2.34 (t, J = 10.8 Hz, 2H), 2.20 (t, J = 11.9 Hz, 4H),2.08 (s, 3H), 1.88 (d, J = 11.5 Hz, 2H), 1.65 (dd, J = 14.2, 7.8 Hz,4H), 1.55 (d, J = 13.6 Hz, 3H), 1.47 (dd, J = 14.8, 7.4 Hz, 2H), 0.99(t, J = 7.3 Hz, 3H); MS m/z 598.4 (M + 1). 45

UNC1146A ++++ ¹H NMR (400 MHz, CDCl₃) δ 8.93 (s, 1H), 8.07-7.97 (m, 2H),7.96- 7.89 (m, 2H), 5.40 (bs, 1H), 4.73-4.58 (m, 1H), 3.91-3.76 (m, 1H),3.52 (dd, J = 12.9, 6.9 Hz, 2H), 3.01 (s, 3H), 2.30-2.14 (m, 4H), 2.07(d, J = 10.8 Hz, 2H), 1.68-1.44 (m, 7H), 1.38 (d, J = 4.8 Hz, 9H), 0.99(t, J = 7.3 Hz, 3H); MS m/z 515.3 (M + 1). 46

UNC1147A ++++ ¹H NMR (400 MHz, CDCl₃) δ 8.94 (s, 1H), 8.07 (d, J = 8.4Hz, 2H), 7.88 (d, J = 8.3 Hz, 2H), 5.34 (bs, 1H), 4.73-4.59 (m, 1H),3.90-3.76 (m, 1H), 3.52 (dd, J = 13.0, 6.8 Hz, 2H), 2.75 (s, 6H), 2.29-2.15 (m, 4H), 2.13-2.02 (m, 2H), 1.66 (dt, J = 14.9, 7.3 Hz, 2H),1.59-1.52 (t, J = 10.2 Hz, 3H), 1.47 (dd, J = 15.0, 7.4 Hz, 2H), 1.00(t, J = 7.3 Hz, 3H); MS m/z 473.3 (M + 1). 47

UNC1148A ++++ ¹H NMR (400 MHz, CDCl₃) δ 8.96 (s, 1H), 8.11 (d, J = 8.3Hz, 2H), 7.95 (d, J = 8.2 Hz, 2H), 5.33 (s, 1H), 4.75-4.57 (m, 1H),3.92-3.74 (m, 5H), 3.53 (dd, J = 13.1, 6.7 Hz, 2H), 2.32-2.16 (m, 4H),2.15- 2.03 (m, 4H), 1.66 (dt, J = 14.8, 7.2 Hz, 2H), 1.55- 1.50 (m, 3H),1.45 (dd, J = 14.6, 7.3 Hz, 2H), 1.00 (t, J = 7.3 Hz, 3H); MS m/z 485.3(M + 1). 48

UNC1149A ++++ ¹H NMR (400 MHz, CDCl₃) δ 8.87 (s, 1H), 7.64-7.55 (m, 2H),7.02 (t, J = 8.7 Hz, 1H), 5.38 (bs, 1H), 4.69-4.50 (m, 1H), 3.94-3.88(m, 4H), 3.88- 3.77 (m, 1H), 3.51 (dd, J = 13.0, 6.9 Hz, 2H), 3.20- 3.10(m, 4H), 2.29-2.12 (m, 4H), 2.10-1.98 (d, J = 11.8 Hz, 2H), 1.68-1.41(m, 7H), 0.99 (t, J = 7.3 Hz, 3H); MS m/z 469.3 (M + 1). 49

UNC1150A ++++ ¹H NMR (400 MHz, CD₃OD) δ 8.89 (s, 1H), 8.10-8.03 (m, 2H),7.86- 7.79 (m, 2H), 4.68-4.54 (m, 1H), 3.84-3.75 (m, 2H), 3.75-3.67 (m,1H), 3.47 (t, J = 7.1 Hz, 2H), 2.75-2.64 (m, 1H), 2.40 (dt, J = 12.0,6.0 Hz, 2H), 2.24-2.08 (m, 4H), 2.03 (d, J = 11.4 Hz, 2H), 1.92 (d, J=10.3 Hz, 2H), 1.68-1.60 (m, 2H), 1.58-1.48 (m, 4H), 1.44 (dd, J = 15.0,7.5 Hz, 2H), 0.96 (t, J = 7.4 Hz, 3H); MS m/z 528.3 (M + 1). 50

UNC1224A ++++ ¹H NMR (400 MHz, CDCl₃) δ 10.75 (s, 1H), 9.07 (s, 1H),7.99 (d, J = 8.4 Hz, 2H), 7.94 (d, J = 8.4 Hz, 2H), 4.67-4.57 m, 1H),3.88-3.75 (m, 3H), 3.55-3.52 (m, 2H), 3.30 (dd, J = 13.3, 6.7 Hz, 2H),3.06 (t, J = 6.0 Hz, 2H), 2.92-2.82 (m, 2H), 2.24-1.98 (m, 12H), 1.74-1.64 (m, 2H), 1.62-1.52 (m, 2H), 1.49-1.39 (m, 2H), 0.97 (t, J = 7.4 Hz,3H); MS m/z 556.40 (M + 1) 51

UNC1225A ++++ ¹H NMR (400 MHz, CDCl₃) δ 9.03 (s, 1H), 8.00 (d, J = 8.2Hz, 2H), 7.94 (d, J = 8.1 Hz, 2H), 4.64- 4.57 (m, 1H), 3.89 (dd, J =11.3, 4.1 Hz, 2H), 3.79- 3.74 (m, 1H), 3.53-3.47 (m, 4H), 3.41 (d, J =1.6 Hz, 1H), 3.38-3.28 (m, 2H), 3.23 (t, J = 7.2 Hz, 2H), 2.19-2.11 (m,4H), 2.07-1.99 (m, 2H), 1.71- 1.62 (m, 2H), 1.60-1.48 (m, 4H), 1.42 (dt,J = 14.5, 7.4 Hz, 5H), 1.29-1.17 (m, 3H), 0.96 (t, J = 7.3 Hz, 3H) ); MSm/z 614.30 (M + 1). 52

UNC1226A ++++ ¹H NMR (400 MHz, CDCl₃) δ 8.93 (s, 1H), 7.99 (d, J = 8.3Hz, 2H), 7.89 (d, J = 8.3 Hz, 2H), 4.65- 4.51 (m, 1H), 3.83-3.67 (m,1H), 3.49-3.43 (m, 4H), 3.37-3.33 (m, 3H), 2.61-2.55 (m, 1H), 2.19- 2.10(m, 4H), 2.02-1.99 (m, 2H), 1.63 (dt, J = 14.5, 7.1 Hz, 2H), 1.57-1.47(m, 2H), 1.46-1.37 (m, 2H), 0.94 (t, J = 7.3 Hz, 3H), 0.69 (q, J = 6.6Hz, 2H), 0.51-0.38 (m, 2H); MS m/z 542.20 (M + 1). 53

UNC1265A ++++ ¹H NMR (400 MHz, CDCl₃+CD₃OD) δ 9.15 (s, 1H), 8.16-8.10(m, 2H), 8.00-7.93 (m, 2H), 4.70- 4.60 (m, 1H), 3.92-3.81 (m, 1H),3.76-3.65 (m, 1H), 3.55-3.45 (m, 4H), 3.42-3.34 (m, 1H), 3.19- 3.11 (m,2H), 3.06 (td, J = 13.0, 2.6 Hz, 2H), 2.85 (d, J = 15.8 Hz, 3H), 2.49-2.27 (m, 3H), 2.25-2.00 (m, 8H), 1.77-1.62 (m, 4H), 1.59-1.50 (m, 2H),1.45 (dt, J = 14.4, 7.4 Hz, 2H), 0.99 (t, J = 7.4 Hz, 3H); MS m/z 613.40(M + 1). 54

UNC1266A ++++ ¹H NMR (400 MHz, CDCl₃ + CD₃OD) δ 9.19 (s, 1H), 8.19-8.12(m, 2H), 8.00-7.94 (m, 2H), 4.75- 4.68 (m, 1H), 4.06-4.00 (m, 1H),3.92-3.82 (m, 1H), 3.57-3.46 (m, 4H), 3.43-3.35 (m, 1H), 3.27- 3.12 (m,3H), 3.07 (td, J = 13.0, 2.5 Hz, 2H), 2.85 (d, J = 15.3 Hz, 3H), 2.56-2.43 (m, 2H), 2.38 (t, J = 6.7 Hz, 2H), 2.12 (d, J = 14.9 Hz, 2H),2.03-1.94 (m, 3H), 1.86-1.74 (m, 3H), 1.72-1.63 (m, 3H), 1.46 (dq, J =14.5, 7.3 Hz, 2H), 0.99 (t, J = 7.4 Hz, 3H); MS m/z 613.40 (M + 1). 55

UNC1267A ++++ ¹H NMR (400 MHz, CDCl₃ + CD₃OD) δ 9.00 (s, 1H), 7.97 (d, J= 8.3 Hz, 2H), 7.92 (d, J = 7.91 Hz, 2H), 5.10-4.99 (m, 1H), 4.63-4.52(m, 1H), 4.03- 3.92 (m, 2H), 3.88-3.82 (m, 2H), 3.77-3.67 (m, 1H),3.50-3.46 (m, 4H), 3.31-3.27 (m, 3H), 3.18- 3.08 (m, 4H), 3.00-2.89 (m,2H), 2.40-2.33 (m, 2H), 2.30-2.27 (m, 1H), 2.17-2.08 (m, 3H), 2.05- 1.89(m, 4H), 1.69-1.58 (m, 2H), 1.57-1.44 (m, 2H), 1.44-1.37 (m, 2H), 0.93(t, J = 7.3 Hz, 3H); MS m/z 643.40 (M + 1). 56

UNC1268A ++++ ¹H NMR (400 MHz, CDCl₃ + CD₃OD) δ 9.00 (s, 1H), 7.98 (dd,J = 8.4, 4.2 Hz, 2H), 7.90 (dd, J = 11.6, 3.4 Hz, 2H), 4.67- 4.54 (m,1H), 4.06-3.76 (m, 5H), 3.58 (s, 3H), 3.52- 3.42 (m, 4H), 3.31-3.23 (m,2H), 3.17-3.06 (m, 4H), 3.01-2.89 (m, 2H), 2.49-2.39 (m, 2H), 2.37- 2.30(m, 2H), 1.99-1.86 (m, 4H), 1.81-1.69 (m, 3H), 1.66-1.59 (m, 2H), 1.39(dt, J = 14.9, 7.4 Hz, 2H), 0.91 (t, J = 7.4 Hz, 3H); MS m/z 643.40 (M +1). 57

UNC1269A ++++ ¹H NMR (400 MHz, CDCl₃ + CD₃OD) δ 8.95 (s, 1H), 8.06 (d, J= 8.2 Hz, 2H), 7.92 (d, J = 8.1 Hz, 2H), 4.64-4.57 (m, 1H), 3.74-3.67(m, 1H), 3.57- 3.53 (m, 1H), 3.46 (t, J = 7.1 Hz, 2H), 3.13 (t, J = 6.7Hz, 2H), 2.33 (t, J = 6.8 Hz, 2H), 2.26-1.98 (m, 7H), 1.78 (d, J = 10.9Hz, 2H), 1.71-1.60 (m, 4H), 1.54 (dd, J = 19.6, 9.4 Hz, 2H), 1.46-1.41(m, 2H), 1.33-1.21 (m, 3H), 1.17-1.07 (m, 3H), 0.96 (t, J = 7.3 Hz, 3H);MS m/z 598.40 (M + 1). 58

UNC1270A +++ ¹H NMR (400 MHz, CDCl₃ + CD₃OD) δ 8.91 (s, 1H), 8.05-8.00(m, 2H), 7.98-7.92 (m, 2H), 5.72- 5.64 (m, 1H), 5.33 (d, J = 7.5 Hz,1H), 4.78-4.59 (m, 1H), 4.14 (dd, J = 7.6, 4.3 Hz, 1H), 3.93-3.81 (m,1H), 3.75-3.64 (m, 1H), 3.56-3.46 (m, 2H), 3.22 (dd, J = 11.6, 6.2 Hz,2H), 2.58-2.49 (m, 1H), 2.41-2.34 (m, 2H), 2.09- 1.92 (m, 4H), 1.91-1.80(m, 4H), 1.72-1.56(m, 6H), 1.46 (dt, J = 14.7, 7.3 Hz, 3H), 1.31 (dt, J= 15.5, 3.4 Hz, 2H), 1.17-1.04 (m, 3H), 1.01-0.94 (m, 3H); MS m/z 598.40(M + 1). 59

UNC1234A ++++ ¹H NMR (400 MHz, CDCl₃ + CD₃OD) δ 8.80 (s, 1H), 7.59 (d, J= 8.4 Hz, 2H), 6.76 (d, J = 8.4 Hz, 2H), 4.55-4.49 (m, 1H), 3.74-3.69(m, 1H), 3.48 (t, J = 7.1 Hz, 2H), 2.20- 2.04 (m, 4H), 1.98 (d, J = 9.2Hz, 2H), 1.72-1.58 (m, 2H), 1.56-1.45 (m, 2H), 1.42-1.36 (m, 2H), 0.94(t, J = 7.3 Hz, 3H); MS m/z 381.30 (M + 1). 60

UNC1235A +++ ¹H NMR (400 MHz, CDCl₃ + CD₃OD) δ 8.80 (s, 1H), 7.61 (d, J= 8.3 Hz, 2H), 6.79 (d, J = 8.4 Hz, 2H), 4.58-4.52 (m, 1H), 4.05 (s,1H), 3.47 (t, J = 7.2 Hz, 2H), 2.52-2.34 (m, 2H), 1.97 (d, J = 12.0 Hz,2H), 1.79-1.69(m, 4H), 1.63 (dd, J = 14.8, 7.6 Hz, 2H), 1.40 (dq, J =14.5, 7.3 Hz, 2H), 0.93 (t, J = 7.3 Hz, 3H); MS m/z 381.30 (M + 1). 61

UNC1236A ++++ ¹H NMR (400 MHz, CDCl₃ + CD₃OD) δ 8.85 (s, 1H), 7.94 (d, J= 8.4 Hz, 2H), 7.87 (d, J = 8.2 Hz, 2H), 4.60-4.50 (m, 1H), 3.73-3.64(m, 1H), 3.42 (t, J = 7.1 Hz, 2H), 3.30- 3.27 (m, 3H), 2.43 (t, J = 6.1Hz, 2H), 2.14-1.94 (m, 7H), 1.61-1.55 (m, 2H), 1.51-1.44 (m, 2H),1.42-1.33 (m, 3H), 0.90 (t, J = 7.2 Hz, 3H); MS m/z 517.30 (M + 1). 62

UNC1281A ++++ ¹H NMR (400 MHz, CD₃OD) δ 9.14 (s, 1H), 8.16 (d, J = 8.4Hz, 2H), 7.99 (d, J = 8.4 Hz, 2H), 4.71-4.65 (m, 1H), 3.75- 3.68 (m,1H), 3.62 (dd, J = 9.5, 4.8 Hz, 3H), 3.53 (t, J = 6.3 Hz, 3H), 3.48-3.44(m, 2H), 3.20 (t, J = 6.6 Hz, 2H), 2.65 (s, 1H), 2.58 (t, J = 6.6 Hz,2H), 2.29- 2.03 (m, 7H), 1.75-1.63 (m, 3H), 1.59-1.51 (m, 2H), 1.51-1.44(m, 2H), 1.02 (t, J = 7.4 Hz, 3H); MS m/z 586.35 (M + 1). 63

UNC1282 +++ ¹H NMR (400 MHz, CDCl₃) 8 8.86 (s, 1H), 8.03- 7.92 (m, 4H),5.72 (t, J = 6.6 Hz, 1H), 4.70-4.60 (m, 1H), 4.13 (s, 1H), 3.68- 3.60(m, 4H), 3.60-3.46 (m, 5H), 3.39-3.32 (m, 2H), 3.26 (dd, J = 11.3, 6.2Hz, 2H), 2.59-2.45 (m, 4H), 2.06-1.95 (m, 2H), 1.89-1.74 (m, 4H), 1.72-1.62 (m, 2H), 1.50-1.39 (m, 2H), 0.97 (t, J = 7.4 Hz, 3H); MS m/z 586.40(M + 1). 64

UNC1283A ++++ ¹H NMR (400 MHz, CD₃OD) δ 9.03 (s, 1H), 8.15-8.10 (m, 2H),7.98- 7.93 (m, 2H), 4.69-4.60 (m, 2H), 3.74-3.66 (m, 1H), 3.49-3.43 (m,4H), 3.39-3.34 (m, 2H), 3.17 (t, J = 6.8 Hz, 2H), 2.52 (t, J = 6.8 Hz,2H), 2.28- 2.18 (m, 2H), 2.16 2.08 (m, 2H), 2.06-1.98 (m, 2H), 1.70-1.55(m, 5H), 1.55-1.41 (m, 8H), 0.99 (t, J = 7.4 Hz, 3H); MS m/z 584.35(M + 1) 65

UNC1284A ++++ ¹H NMR (400 MHz, CDCl₃ + CD₃OD) δ 8.89 (d, J = 1.6 Hz,1H), 8.02- 7.96 (m, 2H), 7.95-7.89 (m, 2H), 4.71-4.57 (m, 1H), 4.08-4.02(m, 1H), 3.83-3.73 (m, 1H), 3.50- 3.40 (m, 4H), 3.35 (dt, J = 3.3, 1.6Hz, 1H), 3.30- 3.23 (m, 2H), 3.16 (t, J = 5.6 Hz, 2H), 2.54-2.40 (m,2H), 2.28-2.25 (m, 1H), 2.14-2.04 (m, 1H), 2.04-1.87 (m, 3H), 1.86- 1.68(m, 2H), 1.66-1.53 (m, 4H), 1.53-1.36 (m, 6H), 0.93 (td, J = 7.3, 0.7Hz, 3H); MS m/z 584.30 (M + 1). 66

UNC1279A +++ ¹H NMR (400 MHz, CDCl₃ + CD₃OD) δ 8.87 (s, 1H), 7.94-7.90(m, 2H), 7.85-7.76 (m, 4H), 7.17- 7.09 (m, 2H), 4.62-4.51 (m, 1H),3.79-3.71 (m, 1H), 3.48 (t, J = 7.2 Hz, 2H), 2.18 (dt, J = 22.5, 7.1 Hz,4H), 2.06-1.96 (m, 2H), 1.69-1.59 (m, 2H), 1.59-1.47 (m, 2H), 1.47- 1.37(m, 2H), 0.95 (t, J = 7.4 Hz, 3H); MS m/z 503.30 (M + 1). 67

UNC1280A +++ ¹H NMR (400 MHz, CDCl₃ + CD₃OD) δ 8.86 (s, 1H), 7.96-7.88(m, 2H), 7.84-7.72 (m, 4H), 7.17- 7.08 (m, 2H), 4.67-4.53 (m, 1H),4.10-4.02 (m, 1H), 3.46 (td, J = 7.2, 3.3 Hz, 2H), 2.48 (dt, J = 20.7,6.7 Hz, 2H), 2.09-1.94 (m, 3H), 1.85-1.67 (m, 3H), 1.63 (dt, J = 14.8,7.4 Hz, 2H), 1.39 (dq, J = 14.8, 7.4 Hz, 3H), 0.93 (t, J = 7.3, 1.3 Hz,3H); MS m/z 503.30 (M + 1). 68

UNC1309A +++ ¹H NMR (400 MHz, CDCl₃ + CD₃OD) δ 8.83 (s, 1H), 7.81 (d, J= 8.6 Hz, 2H), 7.66 (d, J = 8.5 Hz, 2H), 7.30 (s, 1H), 4.66- 4.54 (m,1H), 3.88-3.77 (m, 1H), 3.51 (dd, J = 12.6, 7.0 Hz, 2H), 2.71 (p, J =8.1 Hz, 1H), 2.26-2.13 (m, 4H), 2.09-2.00 (m, 2H), 2.00-1.88 (m, 4H),1.85-1.73 (m, 2H), 1.71- 1.59 (m, 4H), 1.60-1.50 (m, 2H), 1.49-1.40 (m,2H), 0.98 (t, J = 7.3 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃ + CD₃OD) δ174.86, 155.50, 139.09, 127.47, 119.83, 77.30, 76.98, 76.66, 69.65,55.03, 47.14, 41.28, 34.39, 31.47, 30.51, 29.47, 26.00, 20.09, 13.80; MSm/z 477.30 (M + 1). 69

UNC1310A +++ ¹H NMR (400 MHz, CDCl₃ + CD₃OD) δ 8.83 (s, 1H), 7.81 (d, J= 8.6 Hz, 2H), 7.63 (d, J = 8.5 Hz, 2H), 7.39 (s, 1H), 4.65- 4.54 (m,1H), 4.15-4.05 (m, 1H), 3.49 (dd, J = 12.3, 6.9 Hz, 2H), 2.74-2.65 (m,1H), 2.58-2.44 (m, 2H), 2.03-1.87 (m, 6H), 1.87-1.70 (m, 6H), 1.70- 1.54(m, 4H), 1.44 (dt, J = 14.8, 7.3 Hz, 2H), 0.96 (t, J = 7.3 Hz, 3H); ¹³CNMR (100 MHz, CDCl₃ + CD₃OD) δ 174.66, 155.11, 143.63, 138.71, 128.18,127.44, 119.84, 77.30, 76.99, 76.67, 65.25, 54.89, 46.90, 41.33, 31.84,31.41, 30.52, 26.01, 25.71, 20.09, 13.81; MS m/z 477.35 (M + 1). 70

UNC1311A ++++ ¹H NMR (400 MHz, CDCl₃) δ 8.77 (s, 1H), 7.79 (d, J = 8.6Hz, 2H), 7.66 (d, J = 8.5 Hz, 2H), 7.56 (s, 1H), 4.65-4.55 (m, 1H),3.87-3.77 (m, 1H), 3.56-3.49 (m, 2H), 2.27- 2.13 (m, 4H), 2.09-2.01 (m,2H), 1.68 (dt, J = 14.8, 7.4 Hz, 2H), 1.63-1.51 (m, 3H), 1.50-1.40(m,2H), 1.15-11.10 (m, 2H), 0.99 (t, J = 7.3 Hz, 3H), 0.92-0.85 (m, 2H);¹³C NMR (100 MHz, CDCl₃) δ 155.11, 139.12, 127.51, 119.83, 110.22,106.35, 77.29, 77.18, 76.97, 76.66, 69.55, 55.07, 41.36, 34.29, 31.05,29.39, 20.07, 16.06, 13.76, 8.20; MS m/z 449.30 (M + 1). 71

UNC1312A +++ ¹H NMR (400 MHz, CDCl₃) δ 8.74 (s, 1H), 7.77 (d, J = 8.6Hz, 2H), 7.70 (s, 1H), 7.64 (d, J = 8.5 Hz, 2H), 4.66-4.57 (m, 1H),4.16-4.11 (m, 1H), 3.50 (d, J = 7.2 Hz, 2H), 2.59-2.46 (m, 2H), 2.06-1.97 (m, 2H), 1.87-1.73 (m, 4H), 1.72-1.64 (m, 2H), 1.59-1.51 (m, 1H),1.51-1.39 (m, 2H), 1.14- 1.08 (m, 2H), 0.98 (t, J = 7.4 Hz, 3H),0.91-0.85 (m, 2H); MS m/z 449.30 (M + 1). 72

UNC1313A ++++ ¹H NMR (400 MHz, CDCl₃) δ 8.87 (d, J = 6.3 Hz, 1H), 7.91(d, J = 8.4 Hz, 2H), 7.69 (d, J = 8.6 Hz, 2H), 7.55 (d, J = 8.4 Hz, 2H),7.15 (d, J = 8.6 Hz, 2H), 4.59-4.51 (m, 1H), 3.73-3.65 (m, 1H), 3.53 (s,3H), 3.48-3.47 (t, m, 4H), 3.45-3.40 (m, 2H), 3.15 (s, 3H), 2.16- 2.02(m, 4H), 2.02-1.93 (m, 2H), 1.63-1.54 (m, 2H), 1.53-1.42 (m, 2H),1.42-1.33 (m, 2H), 1.15 (t, J = 7.0 Hz, 3H), 0.91 (t, J = 7.3 Hz, 3H);MS m/z 650.35 (M + 1). 73

UNC1314A ++++ ¹H NMR (400 MHz, CDCl₃) δ 9.02 (s, 1H), 8.09 (d, J = 8.4Hz, 2H), 7.77 (d, J = 8.5 Hz, 2H), 7.62 (d, J = 8.3 Hz, 2H), 7.25 (d, J= 8.6 Hz, 2H), 4.71- 4.65 (m, 1H), 4.06-3.99 (m, 1H), 3.61-3.56 (m, 2H),3.56-3.51 (m, 3H), 3.51-3.43 (m, 3H), 3.24 (s, 3H), 2.55-2.45 (m, 2H),2.03-1.93 (m, 3H), 1.82-1.74 (m, 4H), 1.68- 1.60 (m, 2H), 1.44 (dd, J =14.8, 7.5 Hz, 2H), 1.17 (t, J = 7.0 Hz, 3H), 0.97 (t, J = 7.4 Hz, 3H);MS m/z 650.30 (M + 1). 74

UNC1315A ++++ ¹H NMR (400 MHz, CD₃OD + CDCl₃) δ 8.86 (s, 1H), 7.94-7.88(m, 2H), 7.68-7.62 (m, 2H), 7.57- 7.52 (m, 2H), 7.17-7.12 (m, 2H),4.61-4.52 (m, 1H), 3.75-3.66 (m, 1H), 3.52-3.41 (m, 6H), 3.33- 3.30 (m,3H), 3.16 (s, 3H), 2.18-2.04 (m, 4H), 2.03- 1.93 (m, 2H), 1.82 (dt, J =11.9, 6.0 Hz, 2H), 1.60 (dq, J = 14.8, 7.4 Hz, 2H), 1.55-1.44 (m, 2H),1.43- 1.34 (m, 2H), 0.92 (t, J = 7.3 Hz, 3H); MS m/z 650.35 (M + 1). 75

UNC1316A ++++ ¹H NMR (400 MHz, CD₃OD + CDCl₃) δ 8.82 (d, J = 6.5 Hz,1H), 7.89- 7.82 (m, 2H), 7.61-7.55 (m, 2H), 7.47 (d, J = 8.4 Hz, 2H),7.09-7.03 (m, 2H), 4.56-4.45 (m, 1H), 3.94-3.88 (m, 1H), 3.40- 3.28 (m,6H), 3.21 (s, 3H), 3.18 (dt, J = 4.6, 1.5 Hz, 1H), 3.10-3.06 (m, 3H),2.40-2.27 (m, 2H), 1.95- 1.77 (m, 3H), 1.76-1.68 (m, 2H), 1.66-1.55 (m,2H), 1.51 (dt, J = 14.8, 7.4 Hz, 2H), 1.34-1.24 (m, 2H), 0.82 (t, J =7.3 Hz, 3H); MS m/z 650.30 (M + 1). 76

UNC1317A ++++ ¹H NMR (400 MHz, CD₃OD + CDCl₃ δ 8.85 (s, 1H), 7.95-7.86(m, 2H), 7.70-7.63 (m, 2H), 7.58- 7.50 (m, 2H), 7.17-7.10 (m, 2H),4.59-4.50 (m, 1H), 3.74-3.63 (m, 1H), 3.57 (t, J = 6.8 Hz, 2H), 3.42 (t,J = 7.1 Hz, 2H), 3.28 (dt, J = 3.2, 1.6 Hz, 1H), 3.15 (s, 3H), 2.45-2.32 (m, 2H), 2.16-2.03 (m, 4H), 2.01-1.92 (m, 2H), 1.63-1.54 (m, 2H),1.53-1.43 (m, 2H), 1.41- 1.33 (m, 2H), 0.91 (t, J = 7.4 Hz, 3H); MS m/z674.30 (M + 1). 77

UNC1318A +++ ¹H NMR (400 MHz, CD₃OD + CDCl₃) δ 8.81 (s, 1H), 7.89 (d, J= 8.5 Hz, 2H), 7.65 (d, J = 8.6 Hz, 2H), 7.50 (d, J = 8.5 Hz, 2H), 7.11(d, J = 8.6 Hz, 2H), 4.60-4.51 (m, 1H), 3.99-3.94 (m, 1H), 3.52 (t, J =6.9 Hz, 2H), 3.38 (t, J = 7.1 Hz, 2H), 3.24 (dt, J = 3.3, 1.6 Hz, 1H),3.12 (s, 3H), 2.44-2.28 (m, 4H), 1.94-1.84 (m, 2H), 1.77- 1.60 (m, 4H),1.58-1.50 (m, 2H), 1.38-1.30 (m, 2H), 0.87 (t, J = 7.3 Hz, 3H); MS m/z674.30 (M + 1). 78

UNC1319A +++ ¹H NMR (400 MHz, CD₃OD + CDCl₃) δ 8.84 (s, 1H), 7.90 (d, J= 8.4 Hz, 2H), 7.72-7.67 (m, 2H), 7.53 (d, J = 8.4 Hz, 2H), 7.26-7.21(m, 2H), 7.15- 7.09 (m, 2H), 6.97-6.88 (m, 2H), 4.59-4.49 (m, 1H), 4.47(s, 2H), 3.70- 3.64 (m, 1H), 3.42 (t, J = 7.1 Hz, 2H), 3.27 (dt, J =3.2, 1.6 Hz, 2H), 3.14 (s, 3H), 2.16-2.01 (m, 4H), 2.00-1.90 (m, 2H),1.63- 1.53 (m, 2H), 1.52-1.41 (m, 2H), 1.41-1.31 (m, 2H), 0.90 (t, J =7.3 Hz, 3H); MS m/z 686.30 (M + 1). 79

UNC1320A + ¹H NMR (400 MHz, CD₃OD + CDCl₃) δ 8.81 (d, J = 5.6 Hz, 1H),7.86 (dd, J = 8.3, 6.1 Hz, 2H), 7.69- 7.61 (m, 2H), 7.48 (d, J = 8.4 Hz,2H), 7.18 (dd, J = 8.6, 5.4 Hz, 2H), 7.12- 7.04 (m, 2H), 6.91-6.80 (m,2H), 4.57-4.48 (m, 1H), 4.40 (s, 2H), 3.93 (s, 1H), 3.68-3.59 (m, 1H),3.39-3.32 (m, 2H), 3.20 (dt, J = 3.3, 1.6 Hz, 2H), 2.17-2.11 (m, 1H),1.97- 1.78 (m, 4H), 1.75-1.57 (m, 2H), 1.52 (dt, J = 14.9, 7.3 Hz, 2H),1.39-1.25 (m, 3H), 0.84 (t, J = 7.3 Hz, 3H); MS m/z 686.30 (M + 1). 80

UNC1321A +++ ¹H NMR (400 MHz, CD₃OD + CDCl₃) δ 8.82 (s, 1H), 7.91 (d, J= 8.5 Hz, 2H), 7.64-7.57 (m, 2H), 7.54 (d, J = 8.5 Hz, 2H), 7.21-7.06(m, 4H), 6.94 (t, J = 8.7 Hz, 2H), 4.59- 4.52 (m, 1H), 3.74-3.66 (m,1H), 3.57 (t, J = 7.1 Hz, 2H), 3.43 (t, J = 7.1 Hz, 2H), 3.35 (s, 1H),3.31 (dt, J = 3.3, 1.6 Hz, 3H), 3.18 (s, 2H), 2.84 (t, J = 7.1 Hz, 2H),2.19-2.04 (m, 4H), 2.03-1.93 (m, 2H), 1.63-1.55 (m, 2H), 1.55-1.44 (m,2H), 1.44- 1.34 (m, 2H), 0.92 (t, J = 7.3 Hz, 3H); MS m/z 700.30 (M +1). 81

UNC1322A +++ ¹H NMR (400 MHz, CD₃OD + CDCl₃) δ 8.85 (s, 1H), 7.97-7.89(m, 2H), 7.66-7.58 (m, 2H), 7.58- 7.52 (m, 2H), 7.19-7.09 (m, 4H),6.99-6.90 (m, 2H), 4.66-4.57 (m, 1H), 4.05-4.00 (m, 1H), 3.80- 3.72 (m,1H), 3.57 (t, J = 7.2 Hz, 2H), 3.46-3.40 (m, 2H), 3.33-3.29 (m, 2H),3.17 (d, J = 9.0 Hz, 3H), 2.84 (t, J = 7.2 Hz, 2H), 2.50-2.35 (m, 2H),2.09-1.86 (m, 3H), 1.81- 1.66 (m, 3H), 1.64-1.54 (m, 2H), 1.44-1.35 (m,2H), 0.92 (t, J = 7.3 Hz, 3H); MS m/z 700.30 (M + 1). 82

UNC1323A +++ ¹H NMR (400 MHz, CD₃OD + CDCl₃) δ 8.86 (s, 1H), 7.90 (d, J= 8.3 Hz, 2H), 7.65 (d, J = 8.6 Hz, 2H), 7.53 (d, J = 8.4 Hz, 2H), 7.12(d, J = 8.6 Hz, 2H), 4.60-4.48 (m, 1H), 3.82 (s, 1H), 3.72-3.65 (m, 1H),3.42 (t, J = 7.1 Hz, 2H), 3.35-3.25 (m, 3H), 3.14 (s, 3H), 2.17- 2.01(m, 4H), 2.00-1.91 (m, 2H), 1.78-1.63 (m, 1H), 1.62-1.43 (m, 6H),1.41-1.34 (m, 2H), 1.30- 1.24 (m, 3H), 1.14 (d, J = 15.6 Hz, 1H),0.94-0.86 (m, 3H), 0.82 (t, J = 6.8 Hz, 3H); MS m/z 648.30 (M + 1). 83

UNC1324A +++ ¹H NMR (400 MHz, CD₃OD + CDCl₃) δ 8.78 (s, 1H), 7.92-7.82(m, 2H), 7.65-7.57 (m, 2H), 7.52- 7.44 (m, 2H), 7.11-7.02 (m, 2H),4.60-4.47 (m, 1H), 3.73-3.61 (m, 1H), 3.43-3.29 (m, 2H), 3.29- 3.16 (m,3H), 3.10 (s, 3H), 2.44-2.28 (m, 1H), 2.25- 2.10 (m, 1H), 2.02-1.77 (m,4H), 1.76-1.58 (m, 2H), 1.58-1.42 (m, 4H), 1.42-1.28 (m,2H), 1.28- 1.16(m, 4H), 0.85 (t, J = 7.3 Hz, 3H), 0.82-0.71 (m, 3H); MS m/z 648.30 (M +1). 84

UNC1325A +++ ¹H NMR (400 MHz, CD₃OD + CDCl₃) δ 8.86 (s, 1H), 7.74 (d, J= 8.3 Hz, 2H), 7.37 (d, J = 8.3 Hz, 2H), 5.42 (s, 1H), 4.58- 4.46 (m,1H), 3.72-3.64 (m, 1H), 3.46 (t, J = 7.2 Hz, 2H), 3.31 (dd, J = 3.2, 1.6Hz, 1H), 2.31 (s, 3H), 2.20-2.02 (m, 7H), 2.02- 1.93 (m, 2H), 1.62 (dt,J = 14.8, 7.5 Hz, 2H), 1.54- 1.43 (m, 2H), 1.43-1.31 (m, 2H), 0.92 (t, J= 7.4 Hz, 3H); MS m/z 518.30 (M + 1). 85

UNC1326A ++++ ¹H NMR (400 MHz, CD₃OD + CDCl₃) δ 9.37 (s, 1H), 8.80 (t, J= 8.9 Hz, 1H), 8.51 (s, 1H), 7.71- 7.60 (m, 2H), 7.39-7.25 (m, 2H), 6.83(s, 1H), 5.43 (s, 1H), 5.38 (s, 1H), 4.62 (dt, J = 14.7, 11.9 Hz, 1H),4.13 (s, 1H), 3.88-3.80 (m, 1H), 3.56-3.44 (m, 2H), 2.55-2.33 (m, 2H),2.29 (d, J = 10.9 Hz, 3H), 2.15- 1.89 (m, 6H), 1.78 (d, J = 10.5 Hz,2H), 1.68 (dt, J = 14.9, 7.4 Hz, 2H), 1.43 (dq, J = 14.5, 7.3 Hz, 2H),0.96 (t, J = 7.4 Hz, 3H); MS m/z 518.30 (M + 1). 86

UNC1343A ++++ ¹H NMR (400 MHz, CDCl₃) δ 9.43 (brs, 1H), 8.74 (s, 1H),7.75 (d, J = 8.2 Hz, 2H), 7.36 (d, J = 8.3 Hz, 2H), 6.08 (d, J = 3.2 Hz,1H), 5.42 (d, J = 3.3 Hz, 1H), 4.63-4.54 (m, 1H), 3.84-3.74 (m, 1H),3.55-3.46 (m, 2H), 3.23 (s, 3H), 2.48 (s, 3H), 2.24-2.09 (m, 7H), 2.09-1.98 (m, 2H), 1.73-1.65 (m, 2H), 1.61-1.50 (m, 2H), 1.47-1.39 (m, 2H),0.97 (t, J = 7.4 Hz, 3H); MS m/z 532.40 (M + 1). 87

UNC1344A ++++ ¹H NMR (400 MHz, CDCl₃) δ 9.50 (s, 1H), 8.93 (s, 1H), 7.89(d, J = 8.2 Hz, 2H), 7.83-7.68 (m, 1H), 7.56 (d, J = 8.2 Hz, 2H), 6.21(s, 1H), 5.58 (d, J = 2.3 Hz, 1H), 4.79- 4.68 (m, 1H), 3.99-3.91 (m,1H), 3.67 (t, J = 6.7 Hz, 2H), 2.95-2.83 (m, 2H), 2.39-2.12 (m, 6H),1.89-1.80 (m, 2H), 1.76- 1.65 (m, 2H), 1.63-1.53 (m, 2H), 1.35 (t, J =7.5 Hz, 3H), 1.13 (t, J = 7.4 Hz, 3H); MS m/z 548.30 (M + 1). 88

UNC1345A ++++ ¹H NMR (400 MHz, CDCl₃) δ 8.86 (s, 1H), 7.73 (d, J = 8.3Hz, 2H), 7.35 (d, J = 8.3 Hz, 2H), 5.32 (s, 1H), 4.60-4.49 (m, 1H),4.02-3.96 (m, 1H), 3.54 (s, 3H), 3.44 (t, J = 7.2 Hz, 2H), 2.73-2.58 (m,2H), 2.47-2.33 (m, 2H), 1.99-1.87 (m, 2H), 1.77-1.63 (m, 4H, 1.63- 1.54(m, 2H), 1.41-1.30 (m, 2H), 1.15 (t, J = 7.5 Hz, 3H), 0.89 (dd, J = 8.0,6.7 Hz, 3H); MS m/z 548.30 (M + 1). 89

UNC1346A ++++ ¹H NMR (400 MHz, CDCl₃) δ 8.78 (s, 1H), 7.77 (d, J = 8.2Hz, 2H), 7.37 (d, J = 8.3 Hz, 2H), 5.76 (s, 1H), 5.41 (d, J = 3.1 Hz,1H), 4.64-4.56 (m, 1H), 3.86-3.76 (m, 1H), 3.67 (s, 3H), 3.56-3.47 (m,2H), 3.29 (s, 3H), 2.99 (q, J = 7.4 Hz, 2H), 2.25- 2.11 (m, 4H),2.09-2.01 (m, 2H), 1.73-1.64 (m, 2H), 1.63-1.51 (m, 2H), 1.49-1.41 (m,2H), 1.24 (t, J = 7.4 Hz, 3H), 0.99 (t, J = 7.4 Hz, 3H); MS m/z 562.30(M + 1). 90

UNC1347A ++++ ¹H NMR (400 MHz, CDCl₃ + CD₃OD) δ 8.76 (s, 1H), 7.75 (d, J= 8.0 Hz, 2H), 7.35 (d, J = 8.0 Hz, 2H), 5.91 (s, 1H), 5.38 (s, 1H),4.65-4.55 (m, 1H), 4.12 (s, 1H), 3.65 (s, 3H), 3.50 (s, 2H), 3.26 (s,3H), 2.97 (q, J = 7.3 Hz, 2H), 2.57-2.41 (m, 2H), 2.05- 1.94 (m, 2H),1.88-1.72 (m, 4H), 1.71-1.62 (m, 2H), 1.49-1.39 (m,2H), 1.21 (t, J = 7.3Hz, 3H), 0.96 (t, J = 7.3 Hz, 3H); MS m/z 562.30 (M + 1). 91

UNC1348A ++++ ¹H NMR (400 MHz, CDCl₃ + CD₃OD) δ 9.40 (s, 1H), 8.79 (s,1H), 7.88 (s, 1H), 7.73 (d, J = 8.2 Hz, 2H), 7.40 (d, J = 8.1 Hz, 2H),6.12 (s, 1H), 5.42 (s, 1H), 4.62-4.54 (m, 1H), 3.83-3.75 (m, 1H), 3.60(s, 3H), 3.51 (t, J = 6.8 Hz, 2H), 2.32 (s, 3H), 2.21- 2.10 (m, 4H),2.07-2.00 (m, 2H), 1.73-1.65 (m, 2H), 1.61-1.50 (m, 2H), 1.48-1.37 (m,2H), 0.97 (t, J = 7.4 Hz, 3H); MS m/z 534.30 (M + 1). 92

UNC1349A ++++ ¹H NMR (400 MHz, CDCl₃ + CD₃OD) δ 9.35 (s, 1H), 8.85 (s,1H), 8.45 (s, 1H), 7.68 (d, J = 7.9 Hz, 2H),7.31 (d, J = 7.7 Hz, 2H),6.63 (s, 1H), 5.36 (s, 1H), 4.66-4.56 (m, 1H), 4.14 (s, 1H), 3.64-3.58(m, 1H), 3.56 (s, 2H), 3.55- 3.47 (m, 2H), 2.53-2.36 (m, 2H), 2.28 (s,2H), 2.05- 1.96 (m,2H), 1.83-1.74 (m, 3H), 1.72-1.61(m, 2H), 1.43 (dq, J= 14.6, 7.3 Hz, 2H), 0.96 (t, J = 7.4 Hz, 3H); MS m/z 534.30 (M + 1). 93

UNC1350A ++++ ¹H NMR (400 MHz, CDCl₃ + CD₃OD) δ 9.38 (s, 1H), 8.91 (s,1H), 7.97- 7.90 (m, 4H), 7.57-7.50 (m, 2H), 7.46 (d, J = 9.1 Hz, 1H),7.04-6.96 (m, 2H), 4.67-4.56 (m, 1H), 4.49-4.43 (m, 1H), 3.83- 3.75 (m,1H), 3.50 (t, J = 7.1 Hz, 2H), 2.26-2.11 (m, 5H), 2.09-2.01 (m, 2H),1.70-1.62 (m, 2H), 1.60-1.50 (m, 2H), 1.48- 1.40 (m, 2H), 1.06 (dd, J =6.7, 4.2 Hz, 6H), 0.97 (t, J = 7.3 Hz, 3H); MS m/z 602.30 (M + 1). 94

UNC1351A ++++ ¹H NMR (400 MHz, CDCl₃) δ 9.22 (s, 1H), 8.85 (s, 1H), 7.86(d, J = 4.3 Hz, 4H), 7.54 (dd, J = 8.3, 4.5 Hz, 2H), 7.44 (d, J = 7.8Hz, 1H), 6.96 (t, J = 8.5 Hz, 2H), 4.74 (t, J = 7.9 Hz, 1H), 4.64 (t, J= 10.5 Hz, 1H), 4.15 (s, 1H), 3.57-3.44 (m, 2H), 2.60- 2.45 (m, 2H),2.40-2.25 (m, 1H), 2.03 (d, J = 11.8 Hz, 2H), 1.91-1.73 (m, 4H),1.73-1.61 (m, 2H), 1.50-1.39 (m, 2H), 1.09 (d, J = 4.4 Hz, 6H), 0.98 (t,J = 7.3 Hz, 3H); MS m/z 602.30 (M + 1). 95

UNC1288A ++++ ¹H NMR (400 MHz, CDCl₃) δ 9.09 (bs, 1H), 8.84 (s, 1H),8.04 (d, J = 8.4 Hz, 2H), 7.85 (d, J = 8.5 Hz, 2H), 4.72-4.60 (m, 2H),3.97 (s, 2H), 3.89- 3.79 (m, 1H), 3.59-3.50 (m, 3H), 3.38 (bs, 5H),3.20-3.09 (m, 3H), 2.26- 2.16 (m, 3H), 2.13-2.04 (m, 2H), 1.72 (dt, J =14.9, 7.4 Hz, 2H), 1.58 (dt, J = 16.4, 11.3 Hz, 2H), 1.47 (dq, J = 14.5,7.4 Hz, 2H), 1.00 (t, J = 7.4 Hz, 3H); MS m/z 558.30 (M + 1). 96

UNC1352A ND ¹H NMR (400 MHz, CD₃OD) δ 9.11 (s, 1H), 8.04-7.98 (m, 2H),7.58- 7.52 (m, 2H), 4.65 (tt, J = 11.6, 3.9 Hz, 1H), 4.32 (s, 2H), 4.07(dd, J = 5.8, 4.3 Hz, 2H), 3.85 (dd, J = 5.8, 4.3 Hz, 2H), 3.76-3.67 (m,1H), 3.54 (t, J = 7.1 Hz, 2H), 2.27-2.00 (m, 6H), 1.75-1.65 (m, 2H),1.60-1.43 (m, 4H), 1.02 (t, J = 7.4 Hz, 3H); MS m/z 465.30 (M + 1). 97

UNC1355A ND ¹H NMR (400 MHz, CD₃OD) δ 9.07 (s, 1H), 7.95 (d, J = 8.8 Hz,2H), 7.79 (d, J = 8.8 Hz, 2H), 4.70-4.59 (m, 1H), 3.99 (t, J = 7.1 Hz,2H), 3.73 (ddd, J = 14.8, 9.5, 4.0 Hz, 1H), 3.53 (t, J = 7.1 Hz, 2H),2.64 (t, J = 8.1 Hz, 2H), 2.29-2.10 (m, 6H), 2.05 (d, J = 12.3 Hz, 2H),1.70 (dt, J = 14.8, 7.3 Hz, 2H), 1.61-1.42 (m, 4H), 1.01 (t, J = 7.4 Hz,3H); MS m/z 449.30 (M + 1). 98

UNC1227A ++++ ¹H NMR (400 MHz, CD₃OD + CDCl₃) δ 8.94 (s, 1H), 8.01 (d, J= 8.4 Hz, 2H), 7.93 (d, J = 8.4 Hz, 2H), 4.70-4.50 (m, 1H), 3.78-3.65(m, 1H), 3.57 (t, J = 5.3 Hz, 2H), 3.48 (t, J = 7.1 Hz, 2H), 3.01 (t, J= 5.3 Hz, 2H), 2.24-2.07 (m, 4H), 2.02 (d, J = 11.1 Hz, 2H), 1.70- 1.59(m, 2H), 1.59-1.48 (m, 2H), 1.42 (dt, J = 14.5, 7.4 Hz, 2H), 0.96 (t, J= 7.3 Hz, 3H); MS m/z 489.2 (M + 1). 99

UNC1228A ++++ ¹H NMR (400 MHz, CD₃OD + CDCl₃) δ 8.92 (s, 1H), 8.03 (d, J= 8.7 Hz, 2H), 7.93 (d, J = 8.6 Hz, 2H), 4.69-4.54 (m, 1H), 3.78-3.62(m, 2H), 3.56-3.42 (m, 4H), 3.04 (dd, J = 13.1, 4.6 Hz, 1H), 2.89 (dd, J= 13.1, 6.9 Hz, 1H), 2.24-1.95 (m, 6H), 1.69-1.58 (m, 2H), 1.53 (dd, J =17.4, 6.6 Hz, 2H), 1.44 (dq, J = 14.4, 7.3 Hz, 2H), 0.96 (t, J = 7.4 Hz,3H); MS m/z 519.2 (M + 1). 100 

UNC1229A ++++ ¹H NMR (400 MHz, CD₃OD + CDCl₃) δ 8.92 (s, 1H), 8.03 (d, J= 8.7 Hz, 2H), 7.93 (d, J = 8.6 Hz, 2H), 4.69-4.54 (m, 1H), 3.78-3.62(m, 2H), 3.56-3.42 (m, 4H), 3.04 (dd, J = 13.1, 4.6 Hz, 1H), 2.89 (dd, J= 13.1, 6.9 Hz, 1H), 2.24-1.95 (m, 6H), 1.69-1.58 (m, 2H), 1.53 (dd, J =17.4, 6.6 Hz, 2H), 1.44 (dq, J = 14.4, 7.3 Hz, 2H), 0.96 (t, J = 7.4 Hz,3H); MS m/z 519.2 (M + 1). 101 

UNC1285A ++++ ¹H NMR (400 MHz, CD₃OD) δ 9.16 (s, 1H), 7.80-7.69 (m, 2H),7.26 (t, J = 8.6 Hz, 1H), 4.71- 4.60 (m, 1H), 3.80-3.66 (m, 5H), 3.56(t, J = 7.1 Hz, 2H), 3.36-3.18 (m, 4H), 2.26-2.00 (m, 6H), 1.75-1.66 (m,2H), 1.60- 1.45 (m, 4H), 1.42 (t, J = 7.3 Hz, 3H), 1.02 (t, J = 7.4 Hz,3H); MS m/z 496.4 (M + 1). 102 

UNC1286A +++ ¹H NMR (400 MHz, CDCl₃) δ 8.89 (s, 1H), 7.95- 7.87 (m, 2H),7.32 (dd, J = 8.8, 0.9 Hz, 2H), 5.29 (bs, 1H), 4.68-4.57 (m, 1H),3.89-3.77 (m, 1H), 3.51 (dd, J = 12.9, 7.0 Hz, 2H), 2.29-2.12 (m, 4H),2.06 (d, 2H), 1.70-1.60 (m, 2H), 1.56-1.51 (m, 2H), 1.50-1.40 (m, 2H),0.99 (t, J = 7.3 Hz, 3H); MS m/z 450.2 (M + 1). 103 

UNC1287A ++++ ¹H NMR (400 MHz, CD₃OD) δ 8.97-8.86 (m, 1H), 7.73-7.60 (m,2H), 7.24-7.13 (m, 1H), 4.68- 4.55 (m, 1H), 3.75-3.66 (m, 1H), 3.47 (t,J = 7.1 Hz, 2H), 3.35-3.32 (bs, 8H), 2.28-2.08 (m, 4H), 2.05-1.96 (m,2H), 1.71- 1.60 (m, 2H), 1.58-1.40 (m, 4H), 1.04-0.97 (m, 3H); MS m/z468.3 (M + 1).

Example 8 Efficacy of a Novel Small Molecule MerTK Receptor TyrosineKinase Inhibitor in B-RAF Wild-Type and B-RAF Mutant Melanoma Cell

UNC1062, a novel, orally bioavailable and potent MERTK-selectivesmall-molecule tyrosine kinase inhibitor (TKI) was evaluated inpreclinical models of melanoma, both alone and in combination withvemurafenib (a mutant B-RAF TKI). B-RAF wildtype (HMCB) and B-RAF mutant(G361) cell lines were treated with UNC TKI or vehicle. Downstreamsignaling was evaluated by immunoblotting, and induction of apoptosiswas determined by flow cytometry in cells stained with YO-PRO®-1 iodideand propidium iodide. Alternatively, cells were seeded in mediacontaining UNC1062 or vehicle and colony formation was determined.Treatment with MRX6313induced apoptosis and reduced colony growth inboth B-RAF wild-type and B-RAF mutant cell lines, with concentrations aslow as 300 nM resulting in an almost complete block in colony formation.In addition, MerTK inhibition reduced activation of downstreampro-survival signaling pathways known to play roles in melanoma,including ERK, AKT, and STAT6. Importantly, combined treatment with UNC1062 and vemurafenib completely abrogated these signaling pathways in aBRAF mutant cell line and increased apoptosis relative to the singleagents, consistent with the idea that MerTK inhibition may provideadditional therapeutic advantage when combined with vemurafenib inpatients with B-RAF mutant melanomas. Taken together, these studiesvalidate UNC TKI as a potential treatment for both B-RAF wild-type andB-RAF mutant melanomas and provide data supporting continued developmentof UNC1062 for treatment of melanoma. See, FIG. 7A and FIG. 7B.

Example 9 Inhibition of Murine Melanoma Growth by a Small Molecule MerTyrosine Kinase Inhibitor (MER TKI)

In this example, the activity of a MerTK inhibitor is examined on tumorgrowth in autochthonous murine tumor models. Mer TKI is assessed inimmune-competent, genetically engineered murine models (GEMMs). Activityis tested in RAS-driven, INK4a/Arf null melanoma GEMM (TRIA) mice. Theefficacy of 15 chemotherapeutic and/or targeted regimens in a large(>220) cohort of TRIA mice has previously been tested (Clinical CancerResearch 18:5290, 2012). The overall response is 10% (partial responsesand stable disease). There are no complete responses. A combination ofMEK (AZD 6244) and PI3K/mTOR (BEZ235) inhibitors are the most activeprevious regimen (responses seen in 9/18 mice 50%, with 0 CRs) withmoderate toxicity.

Example 10 Cell Killing by Mer TKIs in Combination with FGFR Inhibition

In this study, the interaction between a novel MerTK-selective smallmolecule tyrosine kinase inhibitor (TKI) and AZD-4547, an FGFR TKI, inNSCLC cell lines is studied. Colo699 (MerTK+, FGFR+) and H226 (MerTK+,FGFR+) NSCLC cells are cultured for 14 days in soft agar in the presenceof Mer TKI and/or AZD-4547, alone or in combination, and colonies arestained and counted. Changes in the activity of downstream signalingpathways, including PI3K/AKT, MEK/ERK, and STAT proteins are evaluatedby immunoblotting.

Example 11 Inhibition of Mer Tyrosine Kinase with a Novel Small MoleculeInhibitor in Mouse Models of ALL

In this example, preclinical testing of Mer TKIs as a potential therapyfor MERTK-expressing ALL is disclosed. Mer TKI inhibition ofphosphorylation/activation of MerTK is tested in 697 B-ALL cells. MerTKIs are tested in several mouse models, including an orthotopic B-ALLxenograft model of minimal residual disease and a similar model ofexistent disease in which leukemia is established for 14 days prior toinitiation of treatment. In both models, tumor burden is measured bybioluminescent imaging.

Example 12 Inhibition of Mer Tyrosine Kinase with a Novel Small MoleculeInhibitor in Pre-Clinical Models of Non-Small Cell Lung Cancer

The effects of Mer TKI treatment on activation of MerTK and relatedmembers of the TAM-family of kinases, Axl and Tyro3, and effects ondownstream proliferative and pro-survival signaling pathways areanalyzed by immunoblot. In addition, Mer TKI-mediated anti-tumoractivity is determined in a panel of NSCLC cell lines using soft-agarand clonogenic assays. Cells are stained with YoPro-1-iodide andpropidium iodide dyes and induction of apoptosis is determined usingflow cytometry. Finally, a subcutaneous murine xenograft model isemployed to determine therapeutic effects in vivo.

Example 13 A Dual FLT-3 and Mer Tyrosine Kinase Small Molecule Inhibitorin Acute Myeloid Leukemia Cell Lines and Patient Samples

FLT-3 and Mer tyrosine kinases have been previously identified aspotential targets in the treatment of acute myeloid leukemia (AML).Expression of FLT-3 internal tandem duplication (ITD) occurs in ˜30-40%of AML patient samples and MerTK overexpression has been detected in˜80-100%. In this example, a novel small molecule inhibitor is testedfor activity against both of these kinases and the growth inhibition orapoptosis of cell lines and patient myeloblasts is examined. In thesestudies, the effects of treatment with MER-TKI are analyzed inFLT3-ITD-positive (Molm-13 and MV4;11) and MERTK-positive (Kasumi-1 andU937) AML cell lines and in primary AML patient samples with variableexpression of FLT3-ITD and MerTK. AML cell lines are also stained withYo-Pro-1 iodide and propidium iodide and analyzed by flow cytometry todetermine induction of apoptosis in response to treatment with Mer TKI.Primary patient samples that are MerTK and/or FLT3-ITD positive areanalyzed in similar assays.

Example 14 Targeted Inhibition of Mer Tyrosine Kinase in the TumorMicroenvironment in a Mouse Model of Breast Cancer

To further investigate the utility of MerTK inhibition in the tumormicroenvironment as a therapeutic strategy, the efficacy of a Mer TKI isevaluated in immunocompetent C57Bl/6 mice implanted orthotopically withPyVmT mammary gland tumor cells. These PyVmT tumors cells do not expressMerTK, AXL or TYRO3.

Example 15 Murine FeCl₃-Induced Carotid Artery Thrombosis Model

6-12-week old C57BL/6 mice (The Jackson Laboratory, Bar Harbor, Me.),are fed low-soy laboratory chow to prevent interactions from genestein,a phytoestrogen with tyrosine kinase inhibitor activity. Approximatelyequal numbers of male and female mice are used for all experiments tolimit any potential skewing of results by sex-based differences inthrombosis. The mice are anesthetized with intraperitoneal sodiumpentobarbital (60-90 mg·kg⁻¹ loading dose, 10 to 20 mg/kg⁻¹ maintenancedose as needed to maintain adequate anesthesia as measured by pawpressure response). The mice are then fixed in the supine position to apolycarbonate experimental platform under a dissecting microscope(Olympus SZ61 Infinity Lite, Olympus Equipment). A rectal temperatureprobe is used in conjunction with a heating pad to monitor and maintaintemperature at 37±1° C. A 2 cm vertical midline ventral cervicalincision is made to expose the trachea, which is then horizontallyincised and cannulated with a rigid endotracheal tube (Harvard MiniVenttype 845, Harvard Apparatus) secured with a 4-0 silk tie, and attachedto a ventilator (Harvard MiniVent type 845, Harvard Apparatus), whichdelivered a 200 μL stroke volume and 80 breaths per minute. The carotidartery is exposed by dissection, allowing for attachment of amicrovascular ultrasonic flow probe (Transonic Flowprobe, TransonicSystems, Ithaca, N.Y.), and the cavity is flooded with NaCl to preventtissue dehydration. A 1 mm×5 mm strip of Parafilm (Pechiney PlasticPackaging, Chicago, Ill.) is placed perpendicular to, and immediatelyposterior to, the artery to separate it from other cavity tissue. NaCl(negative control), Mer TKI (3 mg/kg in NaCl), 2 abciximab (positivecontrol), HD ADPis in NaCl (3 mg/kg MRS2179+3 mg/kg 2-MeSAMP), LD ADPis(1.5 mg/kg MRS2179+1.5 mg/kg 2-MeSAMP), or a combination of Mer TKI andLD ADPis are injected and allowed to circulate for 30 minutes. Thecavity is then dried and a 1.2 mm diameter circle of filter paper(Whatman Ltd, Chippenham, Wiltshire, UK) is saturated with 6% FeCl₃ (˜60μM, Fisher) for 10 seconds, and placed on the artery, proximal to theultrasound probe, for 3 minutes to create the injury. Then, the Parafilmand filter paper are removed, the cavity is flooded with saline, and theflow probe readout is analyzed using LabChart software (AD Instruments,CO Springs, Colo.). Elapsed Time To First (initial) artery Occlusion(TTFO, mean blood flow of 0 mL/min flow for >30 seconds), and totalDuration Of Occlusion time (DOO, mean blood flow <20% of pre-FeCl₃baseline) is measured during the 60 minutes following FeCl₃ application.Values are expressed as mean+/−SEM, with significance determined byunpaired, two-tailed Student's t-test.

Example 16 Effects of FLT3 and MerTK Inhibitors on MerTK Phosphorylationand Downstream Signaling in Acute Myeloid Leukemia Cell Lines

Two cell lines known to express a FLT3-ITD mutation (Molm14 and MV4;11)are treated with a novel FLT3 inhibitor which has high specificity forFLT3. The MV4;11 cell line has low MerTK expression, while the Molm14cell line does not express MerTK. Immunoprecipitation of FLT3-ITDpositive AML cell lines after 1 h treatment with a MerTK inhibitor isanalyzed for phosphorylation of FLT3 (pFLT3) in comparison to totalFLT3. Phosphorylation of downstream signaling proteins STAT5, AKT, andERK1/2 in comparison to DMSO and control TKI are also analyzed. Inaddition, an AML cell line that expresses MerTK and does not haveactivating mutations in FLT3 (U937, Kasumi-1) is also used to determineabrogation of activation of intracellular signaling pathways downstreamof FLT3 and MerTK, including AKT and ERK1/2, when treated with MerTKinhibitors. Signaling in AML cell lines is analyzed after 1 hr treatmentwith MerTK inhibitors. Whole cell lysates or IPs are resolved on 8%Tris-Glycine SDS-PAGE gels, then transferred to a nitrocellulosemembrane, which are probed for phospho-proteins. Blots are then strippedand re-probed for the total protein, or actin (loading control).

Example 17 Effect of MerTK Inhibitors on Apoptosis in Acute MyeloidLeukemia Cell Lines

AML cell lines are plated in equal number in soft agar, then colonynumber analyzed after incubation at 37° C. for 14 days. Colonies arecounted using a Gel Count automated colony counter. AML cell lines aretreated for 72 h with MerTK and apoptosis is analyzed after stainingwith Yo-Pro-1 iodide and propidium iodide and undergoing flow cytometricanalysis.

Example 18 MerTK Inhibitors in a Molm14 Xenograft Model (FLT3-ITD AML)

A Molm14 xenograft is established by injection of 2.5×10⁶ cells into NSGmice via tail vein. On day 4 after injection mice are started on dailytherapy with a MerTK inhibitor or saline via oral gavage. Mice aretreated through day 100 then observed for relapse.

Example 19 MerTK Inhibitors in a Patient-Derived Xenograft Model(FLT3-ITD AML)

A patient-derived xenograft model is established with cells from apatient with FLT3-ITD+ AML. NSG mice are sublethally irradiated and then5×10⁶ cells are injected via tail vein. Mice are started on therapy inthe same fashion as described in Example 13 once peripheral blast countsreached ˜10%.

Example 20 MerTK Inhibitors in FLT3-ITD AML Cell Lines withAC220-Resistance Mutations (D835Y and F691L)

Two cell line derivatives of the human FLT3-ITD AML cell line Molm14,which acquired either the D835Y (activation loop) or F691L (gatekeeper)mutation after selection in escalating doses of the FLT3 inhibitorAC220, are used to test the activity of MerTK inhibitors againstclinically relevant FLT3 point mutations. Cells are analyzed forviability after 48 hours of culture in Molm14, Molm14:D835Y, andMolm14:F691L after treatment with a MerTK inhibitor. Phosphorylation isanalyzed in Molm14, Molm14:D835Y, and Molm14:F691L after treatment witha MerTK inhibitor. Cell lines are also analyzed for resistance totreatment with AC220 at concentrations (e.g. 20-fold higher) than theinhibitory concentration in the parental line.

Example 21 MerTK Inhibitors in Molm14 Xenograft Model (FLT3-ITD AML)with AC220-Resistance Mutations (D835Y and F691L)

A Molm14:D835Y xenograft model is established by injection of 2.5×10⁶Molm14:D835Y cells into NSG mice via tail vein. The D835Y mutation inthe activation loop confers resistance to the FLT3 inhibitor AC220. Onday 4 after injection, mice are started on daily therapy with a MerTKinhibitor, 10 mg/kg AC220, or saline via oral gavage. Mice are treatedthrough day 100 then observed for relapse.

Example 22 MerTK, Axl, Tyro3, and Flt3 Kinase Activity of ActiveCompounds

Inhibition constants of MerTK, Flt3, Tyro3 and Axl kinase activity by anactive compound as described herein is determined at the Km for ATPusing a microfluidic capillary electrophoresis (MCE) assay in whichphosphorylated and unphosphorylated substrate peptides were separatedand analyzed using a LabChip EZ Reader. See, Liu J, et al. UNC1062, anew and potent MerTK inhibitor. Eur J Med Chem. 2013; 65:83-93; Liu J,et al. Discovery of novel small molecule MerTK kinase inhibitors for thetreatment of pediatric acute lymphoblastic leukemia. ACS Med Chem Lett.2012; 3:129-134; Pommereau A, Pap E, Kannt A. Two simple and genericantibody-independent kinase assays: comparison of a bioluminescent and amicrofluidic assay format. J Biomol Screen. 2004; 9: 409-416; Dunne J,Reardon H, Trinh V, Li E, Farinas J. Comparison of on-chip and off-chipmicrofluidic kinase assay formats. Assay Drug Dev Technol. 2004;2:121-129; Bernasconi P, Chen M, Galasinski S, Popa-Burke I, BobashevaA, Coudurier L, Birkos S, Hallam R, Janzen W P. A chemogenomic analysisof the human proteome: application to enzyme families. J Biomol Screen.2007; 12:972-982.

Briefly, activity assays were performed in a 384 well, polypropylenemicroplate in a final volume of 50 μL of 50 mM Hepes, Ph 7.4 containing10 mM MgCl₂, 1.0 mM DTT, 0.01% Triton X-100, 0.1% Bovine Serum Albumin(BSA), containing 1.0 μM fluorescent substrate and ATP at the Km foreach enzyme. All reactions were terminated by addition of 20 μL of 70 mMEDTA. After a 180 min incubation, phosphorylated and unphosphorylatedsubstrate peptides were separated in buffer supplemented with 1×CR-8 ona LabChip EZ Reader equipped with a 12-sipper chip. Data were analyzedusing EZ Reader software. Assay conditions for MCE assays

Kinase  ATP Kinase Peptide Substrate (nM) (uM) Mer5-FAM-EFPIYDFLPAKKK-CONH₂ 2.0 5.0 Axl 5-FAM-KKKKEEIYFFF-CONH₂  120 65Tyro 5-FAM-EFPIYDFLPAKKK-CONH₂ 10 21

TABLE 7 Selectivity of Active Compounds Against MerTK, Axl, Tyro3, andFlt3 Compound_ID IC₅₀ Data (nM) UNC00000353A IC₅₀ Mer 91 nM Axl 177 nMTyro3 1471 nM UNC00000354A IC₅₀ Mer 71 nM Axl 118 nM Tyro3 1125 nMUNC00000391A IC₅₀ Mer 756 nM Tyro3 12822 nM Axl 361 nM UNC00000488ATyro3 989 nM IC₅₀ Mer 73 nM Axl 93 nM UNC00000355A IC₅₀ Mer 117 nM Axl153 nM Tyro3 1545 nM UNC00000356A IC₅₀ Mer 25 nM Axl 36 nM Tyro3 405 nMUNC00000392A IC₅₀ Mer 1398 nM Tyro3 10638 nM Axl 690 nM UNC00000481ATyro3 1008 nM IC₅₀ Mer 75 nM Axl 83 nM UNC00000482A Tyro3 2391 nM IC₅₀Mer 156 nM Axl 249 nM UNC00000492A Tyro3 699 nM IC₅₀ Mer 77 nM Axl 96 nMUNC00000487A Axl 64 nM Tyro3 851 nM IC₅₀ Mer 24 nM UNC00000394A Tyro3574 nM IC₅₀ Mer 168 nM Axl 111 nM UNC00000397A IC₅₀ Mer 100 nM Tyro3 416nM Axl 62 nM UNC00000484A Tyro3 853 nM IC₅₀ Mer 92 nM Axl 89 nMUNC00000485A Tyro3 1633 nM IC₅₀ Mer 388 nM Axl 244 nM UNC00000393A IC₅₀Mer 56 nM Tyro3 123 nM Axl 50 nM UNC00000483A Axl 96 nM Tyro3 1137 nMIC₅₀ Mer 60 nM UNC00000395A IC₅₀ Mer 230 nM Tyro3 1119 nM Axl 183 nMUNC00000396A IC₅₀ Mer 149 nM Tyro3 768 nM Axl 184 nM UNC00000398A IC₅₀Mer 126 nM Tyro3 545 nM Axl 128 nM UNC00000399A IC₅₀ Mer 49 nM Tyro3 306nM Axl 62 nM UNC00000491A Tyro3 1304 nM IC₅₀ Mer 172 nM Axl 141 nMUNC00000480A Tyro3 1652 nM IC₅₀ Mer 177 nM Axl 258 nM UNC00000400A Tyro30 nM IC₅₀ Mer 3093 nM Axl 4880 nM UNC00000410A IC₅₀ Mer 5027 nM Tyro330000 nM Axl 769 nM UNC00000411A IC₅₀ Mer 977 nM Tyro3 11179 nM Axl 1014nM UNC00000490A Tyro3 5369 nM IC₅₀ Mer 531 nM Axl 755 nM UNC00000479ATyro3 4304 nM IC₅₀ Mer 341 nM Axl 614 nM UNC00000489A Axl 59 nM Tyro3740 nM IC₅₀ Mer 57 nM UNC00000563A IC₅₀ Mer 18 nM Tyro3 256 nM Axl 14 nMUNC00000564A IC₅₀ Mer 30 nM Tyro3 635 nM Axl 36 nM UNC00000569A IC₅₀ Mer2.9 nM Tyro3 48 nM Axl 37 nM UNC00000570A IC₅₀ Mer 1.8 nM Tyro3 14 nMAxl 12 nM UNC583A Axl 4 nM Tyro3 2.9 nM IC₅₀ Mer 0.25 nM UNC582A Axl 14nM Tyro3 11 nM IC₅₀ Mer 0.95 nM UNC00000548A IC₅₀ Mer 2996 nM Tyro321659 nM Axl 5499 nM UNC580A IC₅₀ Mer 3 nM Tyro3 150 nM Axl 16 nMUNC586A IC₅₀ Mer 0.76 nM Tyro3 22 nM Axl 3.7 nM UNC607A IC₅₀ Mer 0.14 nMTyro3 5.9 nM Axl 1.4 nM UNC608A Axl 2.9 nM Tyro3 29 nM IC₅₀ Mer 0.55 nMUNC595A IC₅₀ Mer 41 nM Tyro3 270 nM Axl 149 nM UNC593A Axl 30 nM Tyro361 nM IC₅₀ Mer 8.1 nM UNC594A IC₅₀ Mer 15 nM Tyro3 214 nM Axl 71 nMUNC602A Axl 99 nM Tyro3 394 nM IC₅₀ Mer 31 nM UNC603A Axl 18 nM Tyro3 46nM IC₅₀ Mer 8 nM UNC600A IC₅₀ Mer 18 nM Tyro3 150 nM Axl 364 nM UNC606AIC₅₀ Mer 16 nM Tyro3 59 nM Axl 167 nM UNC601A IC₅₀ Mer 4.5 nM Tyro3 15nM Axl 46 nM UNC596A IC₅₀ Mer 0 nM Tyro3 30000 nM Axl 30000 nM UNC599AAxl 54 nM Tyro3 335 nM IC₅₀ Mer 44 nM UNC597A IC₅₀ Mer 31 nM Axl 27 nMTyro3 110 nM UNC598A Axl 1192 nM Tyro3 18667 nM IC₅₀ Mer 203 nM UNC604AIC₅₀ Mer 88 nM Tyro3 9994 nM Axl 155 nM UNC605A IC₅₀ Mer 4.5 nM Axl 5.5nM Tyro3 63 nM UNC1056A Axl 215 nM IC₅₀ Mer 9.2 nM Tyro3 85 nM UNC1057ATyro3 127 nM IC₅₀ Mer 20 nM Axl 257 nM UNC1067A Axl 1068 nM IC₅₀ Mer 72nM Tyro3 194 nM UNC782A IC₅₀ Mer 119 nM Axl 30000 nM Tyro3 30000 nMUNC783A IC₅₀ Mer 54 nM Axl 62 nM Tyro3 15175 nM UNC888A Tyro3 296 nMIC₅₀ Mer 74 nM Axl 337 nM UNC886A IC₅₀ Mer 22 nM Tyro3 82 nM Axl 106 nMUNC887A IC₅₀ Mer 15 nM Axl 46 nM Tyro3 183 nM UNC00000544A IC₅₀ Mer 171nM Tyro3 3550 nM Axl 296 nM UNC00000171A IC₅₀ Mer 319 nM Tyro3 10467 nMAxl 1925 nM UNC00000263A Axl 2466 nM IC₅₀ Mer 603 nM Tyro3 7825 nMUNC00000264A Tyro3 30030 nM Axl 30030 nM IC₅₀ Mer 4002 nM UNC00000462AAxl 683 nM IC₅₀ Mer 281 nM Tyro3 2166 nM UNC00000414A IC₅₀ Mer 230 nMAxl 133 nM Tyro3 30000 nM UNC00000415A IC₅₀ Mer 540 nM Tyro3 3833 nM Axl348 nM UNC00000514A Tyro3 3053 nM IC₅₀ Mer 323 nM Axl 406 nMUNC00000515A Tyro3 2459 nM IC₅₀ Mer 292 nM Axl 294 nM UNC00000516A Tyro35179 nM IC₅₀ Mer 366 nM Axl 513 nM UNC00000568A IC₅₀ Mer 28 nM Tyro315000 nM Axl 4032 nM UNC00000556A IC₅₀ Mer 1665 nM Tyro3 17399 nM Axl5256 nM UNC00000547A IC₅₀ Mer 196 nM Tyro3 2131 nM Axl 632 nMUNC00000571A IC₅₀ Mer 482 nM Tyro3 5582 nM Axl 620 nM UNC00000349A IC₅₀Mer 2842 nM Axl 22495 nM Tyro3 74937 nM UNC00000350A Axl 7812 nM Tyro317419 nM IC₅₀ Mer 1054 nM UNC00000351A IC₅₀ Mer 2550 nM Axl 61430 nMTyro3 76104 nM UNC00000352A IC₅₀ Mer 11026 nM Axl 44860 nM Tyro3 75801nM UNC00000346A IC₅₀ Mer 74 nM Axl 1355 nM Tyro3 368 nM UNC00000466AIC₅₀ Mer 474 nM Tyro3 874 nM Flt3 661 nM Axl 5637 nM UNC00000465A IC₅₀Mer 130 nM Tyro3 506 nM Flt3 35 nM Axl 3498 nM UNC00000347A IC₅₀ Mer 95nM Tyro3 521 nM Flt3 28 nM Axl 4091 nM UNC00000348A 19410 nM IC₅₀ Mer412 nM Tyro3 878 nM Flt3521 nM UNC00000345A IC₅₀ Mer 1399 nM Axl 17798nM Tyro3 5648 nM UNC00000470A Axl 17168 nM IC₅₀ Mer 4489 nM Tyro3 16783nM UNC00000261A IC₅₀ Mer 205 nM Tyro3 3532 nM Axl 187 nM UNC00000262ATyro3 2840 nM Axl 83 nM IC₅₀ Mer 209 nM UNC00000343A IC₅₀ Mer 13 nM Axl181 nM Tyro3 80 nM UNC00000344A IC₅₀ Mer 5.9 nM Tyro3 60 nM Axl 85 nMUNC00000463A Axl 47 nM IC₅₀ Mer 14 nM Tyro3 77 nM UNC00000461A Axl 30000nM IC₅₀ Mer 30000 nM Tyro3 30000 nM UNC00000475A Axl 28 nM IC₅₀ Mer 6.5nM Tyro3 137 nM UNC00000464A Axl 46 nM IC₅₀ Mer 12 nM Tyro3 272 nMUNC00000467A Axl 724 nM IC₅₀ Mer 132 nM Tyro3 546 nM UNC00000468A Axl859 nM IC50 Mer 91 nM Tyro3 356 nM UNC00000469A Axl 662 nM IC₅₀ Mer 139nM Tyro3 252 nM UNC00000473A Axl 30000 nM IC₅₀ Mer 30000 nM Tyro3 30000nM UNC00000474A Axl 30000 nM IC₅₀ Mer 21752 nM Tyro3 26915 nMUNC00000573A IC₅₀ Mer 10 nM Tyro3 371 nM Axl 38 nM UNC00000472A Axl 41nM IC₅₀ Mer 13 nM Tyro3 18 nM UNC00000471A Axl 38 nM IC₅₀ Mer 8.2 nMTyro3 75 nM UNC00000546A IC₅₀ Mer 9.5 nM Tyro3 356 nM Axl 54 nMUNC00000551A IC₅₀ Mer 7.6 nM Tyro3 276 nM Axl 40 nM UNC00000554A IC₅₀Mer 220 nM Tyro3 1509 nM Axl 433 nM UNC00000550A IC₅₀ Mer 182 nM Tyro32604 nM Axl 423 nM UNC00000549A IC₅₀ Mer 21 nM Tyro3 301 nM Axl 114 nMUNC00000555A IC₅₀ Mer 56 nM Tyro3 1136 nM Axl 216 nM UNC00000574A IC₅₀Mer 96 nM Tyro3 1791 nM Axl 265 nM UNC00000552A IC₅₀ Mer 4.4 nM Tyro3 93nM Axl 39 nM UNC00000553A IC₅₀ Mer 11 nM Tyro3 123 nM Axl 63 nMUNC00000572A IC₅₀ Mer 47 nM Tyro3 892 nM Axl 397 nM UNC00000265A Axl1055 nM Tyro3 17639 nM IC₅₀ Mer 848 nM UNC00000266A Axl 383 nM Tyro313126 nM IC₅₀ Mer 859 nM UNC00000297A Axl 5299 nM Tyro3 30000 nM IC₅₀Mer 4552 nM UNC00000298A Axl 2772 nM Tyro3 30000 nM IC₅₀ Mer 2643 nMUNC00000267A Tyro3 11082 nM IC₅₀ Mer 1463 nM Axl 14669 nM UNC00000299AIC₅₀ Mer 6969 nM Tyro3 30000 nM Axl 4566 nM UNC00000268A Tyro3 30000 nMIC₅₀ Mer 3734 nM Axl 4360 nM UNC00000300A IC₅₀ Mer 27923 nM Tyro3 30000nM Axl 30000 nM UNC00000269A Tyro3 23111 nM IC₅₀ Mer 1057 nM Axl 2693 nMUNC00000270A Tyro3 30030 nM Axl 30030 nM IC₅₀ Mer 9583 nM UNC999A Tyro3437 nM Axl 30000 nM IC₅₀ Mer 4971 nM UNC1000A Tyro3 30000 nM Axl 30000nM IC₅₀ Mer 0 nM UNC1001A Tyro3 342 nM Axl 30000 nM IC₅₀ Mer 30000 nMUNC1353A IC₅₀ Mer 14 nM Axl 327 nM Tyro3 74 nM UNC1354A IC₅₀ Mer 5 nMAxl 197 nM Tyro3 743 nM UNC1060A Axl 178 nM IC₅₀ Mer 12 nM Tyro3 151 nMUNC1040A IC₅₀ Mer 499 nM Axl 1532 nM Tyro3 7820 nM UNC1058A Tyro3 92 nMIC₅₀ Mer 8.7 nM Axl 197 nM UNC1062A Tyro3 57 nM Axl 84 nM IC₅₀ Mer 1.1nM UNC1063A Axl 122 nM Tyro3 81 nM IC₅₀ Mer 3 nM UNC1066A Tyro3 38 nMIC₅₀ Mer 1.1 nM Axl 75 nM UNC1003A Tyro3 196 nM Axl 275 nM IC₅₀ Mer 12nM UNC1170A Axl 82 nM Tyro3 31 nM IC₅₀ Mer 2.5 nM UNC1179A IC₅₀ Mer 4.5nM Tyro3 43 nM Axl 145 nM UNC1171A Tyro3 13 nM Axl 42 nM IC₅₀ Mer 0.89nM UNC1180A IC₅₀ Mer 1.5 nM Tyro3 30 nM Axl 79 nM UNC1172A Tyro3 27 nMAxl 108 nM IC₅₀ Mer 2.7 nM UNC1173A Tyro3 25 nM Axl 81 nM IC₅₀ Mer 2 nMUNC1181A IC₅₀ Mer 5.9 nM Tyro3 57 nM Axl 215 nM UNC1182A IC₅₀ Mer 4.3 nMTyro3 34 nM Axl 96 nM UNC1183A IC₅₀ Mer 2.2 nM Tyro3 35 nM Axl 104 nMUNC1095A Tyro3 55 nM Axl 61 nM IC₅₀ Mer 2.1 nM UNC1096A Tyro3 54 nM Axl64 nM IC₅₀ Mer 2.7 nM UNC1120A Axl 65 nM IC₅₀ Mer 3.3 nM Tyro3 58 nMUNC1124A Axl 271 nM IC₅₀ Mer 18 nM Tyro3 171 nM UNC1125A Axl 3146 nMIC₅₀ Mer 9.3 nM Tyro3 7626 nM UNC1137A IC₅₀ Mer 18 nM Tyro3 316 nM Axl783 nM UNC1138A Tyro3 321 nM IC₅₀ Mer 11 nM Axl 413 nM UNC1174A Tyro3155 nM Axl 73 nM IC₅₀ Mer 1.4 nM UNC1175A Tyro3 47 nM Axl 55 nM IC₅₀ Mer1.1 nM UNC1176A Tyro3 76 nM Axl 99 nM IC₅₀ Mer 3.5 nM UNC1177A Tyro3 203nM Axl 442 nM IC₅₀ Mer 4 nM UNC1178A Tyro3 11 nM Axl 24 nM IC₅₀ Mer 0.65nM UNC1184A IC₅₀ Mer 3.3 nM Tyro3 88 nM Axl 268 nM UNC1185A IC₅₀ Mer 3nM Tyro3 49 nM Axl 225 nM UNC1186A IC₅₀ Mer 2.3 nM Tyro3 42 nM Axl 83 nMUNC1187A IC₅₀ Mer 5.2 nM Tyro3 1925 nM Axl 30000 nM UNC1188A IC₅₀ Mer3.4 nM Tyro3 66 nM Axl 148 nM UNC1189A IC₅₀ Mer 16 nM Tyro3 134 nM Axl281 nM UNC1190A IC₅₀ Mer 5.3 nM Tyro3 198 nM Axl 247 nM UNC1191A IC₅₀Mer 23 nM Tyro3 271 nM Axl 570 nM UNC1192A IC₅₀ Mer 4.8 nM Tyro3 91 nMAxl 154 nM UNC1193A IC₅₀ Mer 18 nM Tyro3 154 nM Axl 232 nM UNC1222A IC₅₀Mer 2.3 nM Tyro3 67 nM Axl 243 nM UNC1223A IC₅₀ Mer 19 nM Tyro3 202 nMAxl 2682 nM UNC1142A IC₅₀ Mer 0.71 nM Tyro3 12 nM Axl 14 nM UNC1143ATyro3 15 nM IC₅₀ Mer 0.86 nM Axl 11 nM UNC1144A IC₅₀ Mer 0.7 nM Tyro34.8 nM Axl 12 nM F1t3 0.67 nM UNC1145A IC₅₀ Mer 1.6 nM Tyro3 32 nM Axl37 nM UNC1146A IC₅₀ Mer 1.2 nM Tyro3 155 nM Axl 113 nM UNC1147A IC₅₀ Mer1.8 nM Tyro3 47 nM Axl 71 nM UNC1148A Tyro3 41 nM IC₅₀ Mer 1 nM Axl 42nM UNC1149A IC₅₀ Mer 4.6 nM Tyro3 134 nM Axl 284 nM UNC1150A IC₅₀ Mer3.4 nM Tyro3 28 nM Axl 76 nM F1t33.3 nM UNC1224A IC₅₀ Mer 1.6 nM Tyro324 nM Axl 29 nM UNC1225A IC₅₀ Mer 4.5 nM Tyro3 95 nM Axl 110 nM UNC1226AIC₅₀ Mer 1.2 nM Tyro3 21 nM Axl 43 nM UNC1265A IC₅₀ Mer 2.3 nM Tyro3 96nM Axl 74 nM UNC1266A IC₅₀ Mer 2.2 nM Tyro3 82 nM Axl 60 nM UNC1267AIC₅₀ Mer 1.3 nM Tyro3 88 nM Axl 74 nM UNC1268A IC₅₀ Mer 3.3 nM Tyro3 136nM Axl 103 nM UNC1269A IC₅₀ Mer 3.2 nM Tyro3 78 nM Axl 77 nM UNC1270AIC₅₀ Mer 12 nM Tyro3 177 nM Axl 132 nM UNC1234A IC₅₀ Mer 6.7 nM Tyro3165 nM Axl 254 nM UNC1235A IC₅₀ Mer 24 nM Tyro3 244 nM Axl 412 nMUNC1236A IC₅₀ Mer 2.2 nM Tyro3 150 nM Axl 171 nM UNC1281A IC₅₀ Mer 2.2nM Tyro3 95 nM Axl 67 nM UNC1282A IC₅₀ Mer 3.1 nM Tyro3 60 nM Axl 56 nMUNC1283A IC₅₀ Mer 0.49 nM Tyro3 72 nM Axl 64 nM UNC1284A IC₅₀ Mer 1.2 nMTyro3 103 nM Axl 89 nM UNC1279A IC₅₀ Mer 17 nM Tyro3 798 nM Axl 521 nMUNC1280A IC₅₀ Mer 30 nM Tyro3 969 nM Axl 838 nM UNC1309A IC₅₀ Mer 13 nMTyro3 677 nM Axl 677 nM UNC1310A IC₅₀ Mer 43 nM Tyro3 728 nM Axl 728 nMUNC1311A IC₅₀ Mer 6.2 nM Tyro3 168 nM Axl 168 nM UNC1312A IC₅₀ Mer 25 nMTyro3 409 nM Axl 409 nM UNC1313A IC₅₀ Mer 2.2 nM Tyro3 138 nM Axl 155 nMUNC1314A IC₅₀ Mer 4.8 nM Tyro3 30000 nM Axl 11924 nM UNC1315A IC₅₀ Mer3.2 nM Axl 68 nM Tyro3 54 nM UNC1316A IC₅₀ Mer 4.5 nM Tyro3 71 nM Axl120 nM UNC1317A IC₅₀ Mer 9.4 nM Tyro3 30000 nM Axl 30000 nM UNC1318AIC₅₀ Mer 24 nM Tyro3 19500 nM Axl 30000 nM UNC1319A IC₅₀ Mer 11 nM Axl30000 nM Tyro3 24750 nM UNC1320A IC₅₀ Mer 3486 nM Axl 30000 nM Tyro324750 nM UNC1321A IC₅₀ Mer 13 nM Tyro3 19500 nM Axl 30000 nM UNC1322AIC₅₀ Mer 30 nM Tyro3 13122 nM Axl 30000 nM UNC1323A IC₅₀ Mer 15 nM Tyro319500 nM Axl 30000 nM UNC1324A IC₅₀ Mer 39 nM Tyro3 19500 nM Axl 30000nM UNC1325A IC₅₀ Mer 4.3 nM Tyro3 37 nM Axl 36 nM UNC1326A IC₅₀ Mer 6.8nM Tyro3 69 nM Axl 88 nM UNC1343A IC₅₀ Mer 1.3 nM Axl 77 nM Tyro3 40 nMUNC1344A IC₅₀ Mer 1.9 nM Axl 72 nM Tyro3 52 nM UNC1345A IC₅₀ Mer 4.7 nMAxl 113 nM Tyro3 52 nM UNC1346A IC₅₀ Mer 2.9 nM Axl 97 nM Tyro3 53 nMUNC1347A IC₅₀ Mer 5.1 nM Tyro3 244 nM Axl 197 nM UNC1348A IC₅₀ Mer 1.3nM Axl 35 nM Tyro3 29 nM UNC1349A IC₅₀ Mer 5.6 nM Tyro3 110 nM Axl 160nM UNC1350A IC₅₀ Mer 2 nM Axl 119 nM Tyro3 19 nM UNC1351A IC₅₀ Mer 8.4nM Axl 238 nM Tyro3 41 nM UNC1288A IC₅₀ Mer 1.4 nM Tyro3 97 nM Axl 61 nMUNC1352A IC₅₀ Mer 1.4 nM Axl 79 nM Tyro3 83 nM UNC1355A IC₅₀ Mer 4.8 nMAxl 87 nM Tyro3 96 nM UNC1227A IC₅₀ Mer 2.2 nM Tyro3 41 nM Axl 79 nMUNC1228A IC₅₀ Mer 1.7 nM Tyro3 20 nM Axl 51 nM UNC1229A IC₅₀ Mer 2.7 nMTyro3 30 nM Axl 84 nM UNC1285A IC₅₀ Mer 4.2 nM Tyro3 95 nM Axl 62 nMUNC1286A IC₅₀ Mer 47 nM Tyro3 10643 nM Axl 4358 nM UNC1287A IC₅₀ Mer 8.3nM Tyro3 179 nM Axl 168 nM

The foregoing is illustrative of the present invention, and is not to beconstrued as limiting thereof. The invention is defined by the followingclaims, with equivalents of the claims to be included therein.

The invention claimed is:
 1. A method for treating a host with aninfectious disease, comprising administering an effective amount of acompound of the formula:

wherein: R¹ is aryl such as phenyl optionally substituted 1, 2 or 3times with heterocycloalkylalkyl, which heterocycloalkylalkyl issubstituted or unsubstituted; heterocycloalkylalkyl is a substituent ofthe formula —R′R″; R′ is substituted or unsubstituted C₁-C₂ alkyl, andR″ is a heterocyclo group, such as an optionally substituted piperazineor morpholine group; R² is —R⁵R⁶, where R⁵ is a covalent bond or C₁ toC₃ alkyl and R⁶ is cycloalkyl, heterocycloalkyl, aryl, heteroaryl oralkyl, and wherein R⁶ is optionally substituted from one to two timeswith independently selected polar groups; R³ is —NR⁷R⁸, where R⁷ and R⁸are each independently selected from H, alkyl, arylalkyl; andalkoxyalkyl; and R⁴ is H, loweralkyl, halo, or loweralkoxy; or apharmaceutically acceptable composition, salt, isotopic analog, orprodrug thereof.
 2. A method for treating a host with an infectiousdisease, comprising administering an effective amount of a compound ofthe formula:

wherein: R¹¹ is —R⁹(R¹⁰)_(n), where R⁹ is alkyl, alkenyl, -alkylaryl,heterocyclo, aryl, heteroaryl and R¹⁰ is hydrogen, alkyl, haloalkyl,alkoxyalkyl, —O-alkylaryl, hydroxyalkyl, alkenyl, alkenyloxy, alkynyl,alkynyloxy, cycloalkyl, cycloalkylalkyl, cycloalkoxy,cycloalkylalkyloxy, heterocyclo, heterocycloalkyl,alkylheterocycloalkyl, heterocyclooxy, heterocyclolalkyloxy, aryl,arylalkyl, aryloxy, arylalkyloxy, heteroaryl, alkylheteroaryl, halo,hydroxyl, alkoxy, haloalkoxy, mercapto, alkyl-S(O)_(m)—,haloalkyl-S(O)_(m)—, alkenyl-S(O)_(m)—, alkynyl-S(O)_(m)—,cycloalkyl-S(O)_(m)—, cycloalkylalkyl-S(O)_(m)—, aryl-S(O)_(m)—,arylalkyl-S(O)_(m)—, heterocyclo-S(O)_(m)—, heterocycloalkyl-S(O)_(m)—,amino, carboxy, alkylamino, —(CH₂)_(m)—NHalkyl, —(CH₂)_(m)—N(alkyl)₂,—(CH₂)_(m)—NH(CH₂)_(m)OH, —(CH₂)_(m)—NH(CH₂)_(m)cycloalkyl,—(CH₂)_(m)—NH(CH₂)₂₋₃heterocyclo, —(CH₂)_(m)—NH(CH₂)_(m)aryl,—(CH₂)_(m)—NH(CH₂)₂₋₃heteroaryl, —(CH₂)_(m)NH(CH₂)₂₋₃N(alkyl)₂,alkenylamino, alkynylamino, haloalkylamino, cycloalkylamino,cycloalkylalkylamino, arylamino, arylalkylamino, heterocycloamino,heterocycloalkylamino, disubstitutedamino, acylamino, acyloxy, ester,amide, S(O)₂OR²², CONHNH₂, cyano, nitro, aminosulfonyl, COOH,sulfonamide, urea, alkoxyacylamino, aminoacyloxy, —C(CH₂)₂R²², andwherein R¹⁰ is optionally substituted one, two or three times; m=0, 1, 2or 3; n=0, 1 or 2; R¹² is —R¹⁵R¹⁶, where R¹⁵ is a covalent bond or C₁ toC₃ alkyl and R¹⁶ is cycloalkyl, cycloalkylalkyl, heterocyclo,heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkylhydroxyalkyl, alkoxyalkyl, or alkyl, and wherein R¹⁶ is optionallysubstituted one, two or three times; R¹³ is NR¹⁷R¹⁸, where; R¹⁷ isselected from the group consisting of H, alkyl, haloalkyl, hydroxyalkyl,aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclo,heterocycloalkyl, allcylheterocycloalkyl, heteroaryl, heteroarylalkyl,and alkoxyalkyl, each of which is optionally substituted one, two orthree times; R¹⁸ is selected from the group consisting of H, alkyl,haloalkyl, hydroxyalkyl, aryl, arylalkyl; cycloalkyl, cycloalkylalkyl,heterocyclo, heterocycloalkyl, alkylheterocycloalkyl, heteroaryl,heteroarylalkyl, and alkoxyalkyl, each of which is optionallysubstituted one, two or three times; or R¹⁷ and R¹⁸ together with thenitrogen to which they are bonded can form a heterocyclic group that canbe optionally substituted; R¹⁴ is H, loweralkyl, halo, or loweralkoxy;R²² is selected from alkyl, alkenyl, alkynyl, aryl, arylalkyl,cycloalkyl, cycloalkylalkyl, heterocyclo, heterocycloalkyl, heteroaryl,or heteroarylalkyl; or a pharmaceutically acceptable salt, thereof. 3.The method of claim 1, wherein the infectious disease is a viralinfection.
 4. The method of claim 2, wherein the infectious disease is aviral infection.
 5. The method of claim 1, wherein the infectiousdisease is a bacterial infection.
 6. The method of claim 2, wherein theinfectious disease is a bacterial infection.
 7. The method of claim 3 or4, wherein the virus is selected from the group consisting of whereinthe virus is selected from the group consisting of a Flavivirus,Hepacivirus, Pegivirus, Pestivirus, Filovirus, Togavirus, Coronavirus,Orthomyxovirus, Paramyxovirus, Calicivirus, and Lentivirus.
 8. Themethod of claim 7, wherein the virus is Chikungunya.
 9. The method ofclaim 7, wherein the virus is HCV.
 10. The method of claim 7, whereinthe virus is HIV.
 11. The method of claim 5 or 6, wherein the bacterialdisease is selected from the group consisting of Escherichia coli,Staphylococcus aureus, Enterococcus faecalis, and Streptococcuspneumoniae.
 12. A method for treating a host with a medical disorder inneed of immunosuppressive adjunctive therapy in combination with adirect acting drug for the medical disorder, comprising administering anadjunctively immunosuppressive effective amount of a compound of theformula:

wherein: R¹ is aryl such as phenyl optionally substituted 1, 2 or 3times with heterocycloalkylalkyl, which heterocycloalkylalkyl issubstituted or unsubstituted; heterocycloalkylalkyl is a substituent ofthe formula —R′R″; R′ is substituted or unsubstituted C₁-C₂ alkyl, andR″ is a heterocyclo group, such as an optionally substituted piperazineor morpholine group; R² is —R⁵R⁶, where R⁵ is a covalent bond or C₁ toC₃ alkyl and R⁶ is cycloalkyl, heterocycloalkyl, aryl, heteroaryl oralkyl, and wherein R⁶ is optionally substituted from one to two timeswith independently selected polar groups; R³ is —NR⁷R⁸, where R⁷ and R⁸are each independently selected from H, alkyl, arylalkyl; andalkoxyalkyl; and R⁴ is H, loweralkyl, halo, or loweralkoxy; or apharmaceutically acceptable composition, salt, isotopic analog, orprodrug thereof.
 13. A method for treating a host with a medicaldisorder in need of immunosuppressive adjunctive therapy in combinationwith a direct acting drug for the medical disorder, comprisingadministering an adjunctively immunosuppressive effective amount of acompound of the formula:

wherein: R¹¹ is —R⁹(R¹⁰)_(n), where R⁹ is alkyl, alkenyl, -alkylaryl,heterocyclo, aryl, heteroaryl and R¹⁰ is hydrogen, alkyl, haloalkyl,alkoxyalkyl, —O-alkylaryl, hydroxyalkyl, alkenyl, alkenyloxy, alkynyl,alkynyloxy, cycloalkyl, cycloalkylalkyl, cycloalkoxy,cycloalkylalkyloxy, heterocyclo, heterocycloalkyl,alkylheterocycloalkyl, heterocyclooxy, heterocyclolalkyloxy, aryl,arylalkyl, aryloxy, arylalkyloxy, heteroaryl, alkylheteroaryl, halo,hydroxyl, alkoxy, haloalkoxy, mercapto, alkyl-S(O)_(m)—,haloalkyl-S(O)_(m)—, alkenyl-S(O)_(m)—, alkynyl-S(O)_(m)—,cycloalkyl-S(O)_(m)—, cycloalkylalkyl-S(O)_(m)—, aryl-S(O)_(m)—,arylalkyl-S(O)_(m)—, heterocyclo-S(O)_(m)—, heterocycloalkyl-S(O)_(m)—,amino, carboxy, alkylamino, —(CH₂)_(m)—NHalkyl, —(CH₂)_(m)—N(alkyl)₂,—(CH₂)_(m)—NH(CH₂)_(m)OH, —(CH₂)_(m)—NH(CH₂)_(m)cycloalkyl,—(CH₂)_(m)—NH(CH₂)₂₋₃heterocyclo, —(CH₂)_(m)—NH(CH₂)_(m)aryl,—(CH₂)_(m)—NH(CH₂)₂₋₃heteroaryl, —(CH₂)_(m)NH(CH₂)₂₋₃N(alkyl)₂,alkenylamino, alkynylamino, haloalkylamino, cycloalkylamino,cycloalkylalkylamino, arylamino, arylalkylamino, heterocycloamino,heterocycloalkylamino, disubstitutedamino, acylamino, acyloxy, ester,amide, S(O)₂OR²², CONHNH₂, cyano, nitro, aminosulfonyl, COOH,sulfonamide, urea, alkoxyacylamino, aminoacyloxy, —C(CH₂)₂R²², andwherein R¹⁰ is optionally substituted one, two or three times; m=0, 1, 2or 3; 0, 1 or 2; R¹² is —R¹⁵R¹⁶, where R¹⁵ is a covalent bond or C₁ toC₃ alkyl and R¹⁶ is cycloalkyl, cycloalkylalkyl, heterocyclo,heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkylhydroxyalkyl, alkoxyalkyl, or alkyl, and wherein R¹⁶ is optionallysubstituted one, two or three times; R¹³ is NR¹⁷R¹⁸, where; R¹⁷ isselected from the group consisting of H, alkyl, haloalkyl, hydroxyalkyl,aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclo,heterocycloalkyl, alkylheterocycloalkyl, heteroaryl, heteroarylalkyl,and alkoxyalkyl, each of which is optionally substituted one, two orthree times; R¹⁸ is selected from the group consisting of H, alkyl,haloalkyl, hydroxyalkyl, aryl, arylalkyl; cycloalkyl, cycloalkylalkyl,heterocyclo, heterocycloalkyl, alkylheterocycloalkyl, heteroaryl,heteroarylalkyl, and alkoxyalkyl, each of which is optionallysubstituted one, two or three times; or R¹⁷ and R¹⁸ together with thenitrogen to which they are bonded can form a heterocyclic group that canbe optionally substituted; R¹⁴ is H, loweralkyl, halo, or loweralkoxy;R²² is selected from alkyl, alkenyl, alkynyl, aryl, arylalkyl,cycloalkyl, cycloalkylalkyl, heterocyclo, heterocycloalkyl, heteroaryl,or heteroarylalkyl; or a pharmaceutically acceptable salt, thereof. 14.A method for treating a host with acute myeloid leukemia (AML) or acutelymphoblastic leukemia (ALL) comprising administering an effectiveamount of the compound of claim
 1. 15. A method for treating a host withacute myeloid leukemia or acute lymphoblastic leukemia comprisingadministering an effective amount of the compound of claim
 2. 16. Themethod of claim 14, wherein the AML or ALL is resistant to prior drugtherapy.
 17. The method of claim 15, wherein the AML or ALL is resistantto prior drug therapy.
 18. The method of claim 14 or 15 wherein the AMLcontains a mutation within the FLT3-TKD at amino acid F691 or D835. 19.The method of claim 2, 13 or 15, wherein the compound is:

wherein: R¹⁹ is heterocycle; R²⁰ and R²¹ are each independentlyhydrogen, alkyl, cycloalkyl, or cycloalkylalkyl.
 20. The method of claim2, 13 or 15 wherein the compound is:


21. The method of claim 2, 13 or 15 wherein the compound is: